Введение
Аутосомно-доминантное генетическое заболевание, связанное с высоким риском развития рака толстой кишки.
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Наследственный неполипозный колоректальный рак (ННПКК) – это наследственная предрасположенность к раку толстой кишки. ННПКК включает (и ранее был синонимом) синдрома Линча, аутосомно-доминантного генетического заболевания, которое связано с высоким риском развития рака толстой кишки, рака эндометрия (второй по распространенности), рака яичников, желудка, тонкой кишки, гепатобилиарного тракта, верхних мочевыводящих путей, головного мозга и кожи. Повышенный риск развития этих видов рака обусловлен унаследованными генетическими мутациями, нарушающими репарацию ДНК. Это тип ракового синдрома. К другим состояниям, связанным с ННПКК, относятся синдром, подобный синдрому Линча, полипоз, связанный с полимеразой, и семейный колоректальный рак типа X. Тип ракаРиск на протяжении жизни (%)Средний возраст на момент постановки диагноза (лет)Колоректальный52–5844–61Эндометриальный25–6048–62Желудочный6–1356Яичника4–1242,5
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Помимо типов рака, указанных в приведенной выше таблице, известно, что синдром Линча также способствует повышенному риску рака тонкой кишки, рака поджелудочной железы, рака мочеточника/почечной лоханки, рака желчных путей, рака головного мозга и себозных новообразований. Средний возраст постановки диагноза колоректального рака составляет 44 года у членов семей, соответствующих амстердамским критериям. Средний возраст постановки диагноза рака эндометрия составляет около 46 лет. Среди женщин с ННПКК, у которых одновременно диагностированы рак толстой кишки и рак эндометрия, примерно у половины первым проявляется рак эндометрия, что делает рак эндометрия наиболее распространенным первичным раком при синдроме Линча. Наиболее распространенным симптомом рака эндометрия является ненормальное вагинальное кровотечение. При ННПКК средний возраст постановки диагноза рака желудка составляет 56 лет, при этом наиболее часто сообщается о аденокарциноме кишечного типа. Средний возраст постановки диагноза рака яичников, связанного с ННПКК, составляет 42,5 года; примерно 30% диагностируются до 40 лет. Значительные различия в частоте возникновения рака были обнаружены в зависимости от вовлеченной мутации. Риски развития различных видов рака до 75 лет в зависимости от мутаций представлены в таблице ниже. ГенРиск развития колоректального ракаРиск развития рака эндометрияРиск развития рака яичниковРиск развития рака верхнего отдела желудочно-кишечного тракта (желудка, двенадцатиперстной кишки, желчных протоков или поджелудочной железы)Риск развития рака мочевыводящих путейРиск развития рака предстательной железыРиск развития опухоли головного мозгаMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a.MSH615%46%13%7%11%18%1%
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
+Риск развития гинекологического рака при синдроме ЛинчаГенРиск развития рака яичниковРиск развития рака эндометрияMLH14–24%25–60%MSH2/EPCAM4–24%25–60%MSH61–11%16–26%PMS26% (общий риск)15%
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Генетика
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Синдром Линча наследуется по аутосомно-доминантному типу. Характерной чертой синдрома Линча является дефектная репарация ДНК, которая вызывает повышенную частоту изменений отдельных нуклеотидов и микросателлитную нестабильность, также известную как MSI-H (H – "высокий"). MSI можно выявить в образцах рака в патологоанатомической лаборатории. В большинстве случаев это приводит к изменениям в длине динуклеотидных повторов нуклеотидных оснований цитозина и аденина (последовательность: CACACACACA). 4 основных гена, участвующих в синдроме Линча, обычно кодируют белки, которые образуют димеры для функционирования: белок MLH1 димеризуется с белком PMS2 для образования MutLα, который координирует связывание других белков, участвующих в репарации, таких как ДНК-геликаза, белок, связывающийся с одноцепочечной ДНК (RPA) и ДНК-полимеразы. Белок MSH2 димеризуется с белком MSH6, который идентифицирует несоответствия посредством модели скользящей защелки, белка для сканирования ошибок. Нарушение любого гена для белкового димера нарушает функцию белка. Эти 4 гена участвуют в коррекции ошибок (репарации), поэтому дисфункция генов может привести к невозможности исправить ошибки репликации ДНК и вызвать синдром Линча. Известно, что синдром Линча связан с другими мутациями в генах, участвующих в пути репарации ДНК:
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Название OMIMГены, связанные с ННПККЧастота мутаций в семьях ННПККЛокусПервая публикацияHNPCC1MSH2/EPCAMприблизительно 60%2p22Fishel 1993HNPCC5MSH67–10%2p16Miyaki 1997HNPCC4PMS2относительно редко7p222q31q33Nicolaides 1994HNPCC6TGFBR2сообщение о случае3p22HNPCC7MLH3оспаривается14q24.3
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Люди с мутациями MSH6 чаще имеют отрицательный результат по амстердамским критериям II. Проявления при MSH6 немного отличаются от проявлений при MLH1 и MSH2, и термин "синдром MSH6" использовался для описания этого состояния. В одном исследовании, руководства Bethesda были более чувствительными, чем амстердамские критерии, для его выявления. До 39% семей с мутациями в гене синдрома Линча не соответствуют амстердамским критериям. Поэтому семьи, у которых обнаружена патогенная мутация в гене синдрома Линча, должны считаться имеющими синдром Линча, независимо от анамнеза семьи. Это также означает, что амстердамские критерии не позволяют выявить многих людей, подверженных риску развития синдрома Линча. Совершенствование критериев скрининга является активной областью исследований, как подробно описано в разделе "Стратегии скрининга" этой статьи. Большинство людей с синдромом Линча наследуют заболевание от родителя. Однако из-за неполной пенетрантности, вариабельного возраста постановки диагноза рака, снижения риска рака или ранней смерти не все люди с мутацией гена синдрома Линча имеют родителя, у которого был рак. У некоторых людей ННПКК развивается de novo в новом поколении, без наследования гена. Этих людей часто выявляют только после развития рака толстой кишки в раннем возрасте. У родителей с ННПКК есть 50% шанс передать генетическую мутацию каждому ребенку. Важно также отметить, что патогенная мутация только в одном из генов MMR недостаточно для развития рака, а для этого необходимы дальнейшие мутации в других генах-супрессорах опухолей.
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Диагностика
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Диагноз синдрома Линча ставится людям с зародышевой мутацией ДНК в одном из генов MMR (MLH1, MSH2, MSH6 и PMS2) или гене EPCAM, выявленной с помощью генетического тестирования. Кандидаты на зародышевое генетическое тестирование могут быть идентифицированы по клиническим критериям, таким как амстердамские клинические критерии и руководства Bethesda, или посредством анализа опухоли с помощью иммуногистохимии (ИГХ) или тестирования на микросателлитную нестабильность (MSI). Генетическое тестирование коммерчески доступно и состоит из анализа крови.
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Иммуногистохимия
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Иммуногистохимия (ИГХ) – это метод, который можно использовать для выявления аномальной экспрессии белков репарации несоответствий (MMR) в опухолях, связанных с синдромом Линча. Хотя он не является диагностическим для синдрома Линча, он может играть роль в выявлении людей, которым следует пройти зародышевое тестирование. Два метода реализации тестирования ИГХ включают тестирование на основе возраста и универсальное тестирование для всех людей. В настоящее время нет широкого согласия относительно того, какой метод скрининга следует использовать. MSI связан с альтернативными по размеру повторяющимися последованиями ДНК, которые отсутствуют в коррелированной зародышевой ДНК, что приводит к 15–20% случаев рака толстой кишки. MSI идентифицируется путем экстракции ДНК как из образца ткани опухоли, так и из образца нормальной ткани с последующим ПЦР-анализом микросателлитных регионов.
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Классификация
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Три основные группы MSI-H (микросателлитная нестабильность – MSI) рака могут быть распознаны по гистопатологическим критериям:
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
* правосторонние малодифференцированные раки
* правосторонние слизистые раки
* аденокарциномы в любом месте, показывающие какой-либо измеримый уровень интраэпителиальных лимфоцитов (TIL)
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Гистопатологические критерии недостаточно чувствительны для выявления MSI по гистологии, но исследователи пытаются использовать искусственный интеллект для прогнозирования MSI по гистологии.
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Скрининг
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Генетическое консультирование и генетическое тестирование рекомендуется семьям, соответствующим амстердамским критериям, предпочтительно до начала рака толстой кишки.
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Рак толстой кишки
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Колоноскопия рекомендуется в качестве профилактического метода наблюдения для людей с синдромом Линча или генами, связанными с LS. В частности, рекомендуется начинать колоноскопию в возрасте 20–25 лет для носителей мутаций MLH1 и MSH2 и в 35 лет для носителей мутаций MSH6 и PMS2. Колоноскопическое наблюдение должно...
Autosomal dominant genetic condition associated with a high risk of cancer in the colon
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary predisposition to colon cancer. HNPCC includes (and was once synonymous with) Lynch syndrome, an autosomal dominant genetic condition that is associated with a high risk of colon cancer, endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited genetic mutations that impair DNA mismatch repair. It is a type of cancer syndrome. Other HNPCC conditions include Lynch like syndrome, polymerase proofreading associated polyposis and familial colorectal cancer type X. Type of cancerLifetime risk (%)Mean age at diagnosis (years)Colorectal52 5844 61Endometrial25 6048 62Gastric6 1356Ovarian4 1242.5
In addition to the types of cancer found in the chart above, it is understood that Lynch syndrome also contributes to an increased risk of small bowel cancer, pancreatic cancer, ureter/renal pelvis cancer, biliary tract cancer, brain cancer, and sebaceous neoplasms. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. The most common symptom of endometrial cancer is abnormal vaginal bleeding. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal type adenocarcinoma being the most commonly reported pathology. HNPCC associated ovarian cancers have an average age of diagnosis of 42.5 years old; approximately 30% are diagnosed before age 40. Significant variation in the rate of cancer has been found depending on the mutation involved. Up to the age of 75 years the risks of different cancers by the mutations are in the table below. Genecolorectal cancer riskendometrial cancer riskovarian cancer riskupper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancer riskurinary tract cancers riskprostate cancer riskbrain tumor riskMLH146%43%10%21%8%17%1%MSH257%17%10%25%32%5%n. a. MSH615%46%13%7%11%18%1%
+Risk of gynecologic cancer in Lynch syndromeGeneOvarian cancer riskEndometrial cancer riskMLH14 24%25 60%MSH2/EPCAM4 24%25 60%MSH61 11%16 26%PMS26% (combined risk)15%
Genetics
Lynch syndrome is inherited in an autosomal dominant fashion. The hallmark of Lynch syndrome is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA ). The 4 main genes involved in Lynch syndrome normally encode for proteins that form dimers to function:
MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single stranded DNA binding protein (RPA), and DNA polymerases. MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause Lynch syndrome. Lynch syndrome is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway:
OMIM nameGenes implicated in HNPCCFrequency of mutations in HNPCC familiesLocusFirst publicationHNPCC1 MSH2/EPCAM approximately 60% 2p22Fishel 1993HNPCC5MSH6 7 10% 2p16Miyaki 1997HNPCC4PMS2 relatively infrequent7p22 2q31 q33 Nicolaides 1994HNPCC6TGFBR2 case report 3p22HNPCC7MLH3 disputed 14q24.3
People with MSH6 mutations are more likely to be Amsterdam criteria II negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in a Lynch syndrome gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in a Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with Lynch syndrome inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an Lynch syndrome gene mutation have a parent who had cancer. Some people develop HNPCC de novo in a new generation, without inheriting the gene. These people are often only identified after developing an early life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur. Diagnosis
A diagnosis of Lynch syndrome is applied to people with a germline DNA mutation in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene, identified by genetic testing. Candidates for germline genetic testing can be identified by clinical criteria such as the Amsterdam Clinical Criteria and Bethesda Guidelines, or through tumor analysis by immunohistochemistry (IHC), or microsatellite instability (MSI) testing. Genetic testing is commercially available and consists of a blood test. Immunohistochemistry
Immunohistochemistry (IHC) is a method that can be used to detect abnormal mismatch repair (MMR) protein expression in tumours that are associated with Lynch syndrome. While it is not diagnostic of a Lynch syndrome, it can play a role in identifying people who should have germline testing. Two methods of implementation of IHC testing includes age based testing and universal testing for all people. Currently, there is no widespread agreement regarding which screening method should be used. MSI is associated with alternate sized repetitive DNA sequences that are not present in the correlated germ line DNA resulting in 15 20% of colorectal cancers. MSI is identified through DNA extraction from both a tumor tissue sample and a normal tissue sample followed by PCR analysis of microsatellite regions. Classification
Three major groups of MSI H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
right sided poorly differentiated cancers
right sided mucinous cancers
adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
The histopathological criteria are not sensitive enough to detect MSI from histology but researchers are trying to use artificial intelligence to predict MSI from histology. Screening
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer. Colon cancerColonoscopies are recommended as a preventative method of surveillance for individuals who have Lynch syndrome, or LS associated genes. Specifically, it is recommended that colonoscopies begin at ages 20–25 for MLH1 and MSH2 mutation carriers and 35 years for MSH6 and PMS2 mutation carriers. Colonoscopic surveillance should then be performed at a 1 2 year interval for Lynch Syndrome patients. For women with Lynch syndrome, a yearly CA 125 blood test can be used to screen for ovarian cancer, however there is limited data on the efficacy of this test in reducing mortality. Other cancers'''
There are also strategies for detecting other cancers early or reducing the chances of developing them that people with Lynch syndrome can discuss with their doctor, however their effectiveness is not clear. These options include:
Upper endoscopies to detect stomach and small bowel cancer every 3–5 years, starting at age 30 at the earliest (preferably in a research setting)Amsterdam I Criteria (all bullet points must be fulfilled): The Amsterdam I criteria were published in 1990; however, were felt to be insufficiently sensitive. Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
Two successive affected generations
One or more colon cancers diagnosed under age 50 years
Familial adenomatous polyposis (FAP) has been excluded
The Amsterdam II criteria were developed in 1999 and improved the diagnostic sensitivity for Lynch syndrome by including cancers of the endometrium, small bowel, ureter and renal pelvis. Amsterdam Criteria II (all bullet points must be fulfilled):
There is an ongoing controversy over the benefit of 5 fluorouracil based adjuvant therapies for Lynch syndrome related colorectal tumours, particularly those in stages I and II. Anti PD 1 antibody therapy can be effective. Checkpoint blockade with anti PD 1 therapy is now preferred first line therapy for advanced Microsatellite Instability–High colorectal cancer.
Эпидемиология
Хотя точная распространенность синдрома Линча, обусловленного мутациями, в общей популяции остается неизвестной, последние исследования оценивают ее в 1 случай на 279 человек, или 0,35%. У некоторых популяций известно о более высокой распространенности основательских мутаций, в том числе, помимо прочих, у французских канадцев, исландцев, афроамериканцев и ашкеназских евреев.
Though the exact prevalence of Lynch syndrome causing mutations in the general population remain unknown, recent studies estimate the prevalence to be 1 in 279 individuals, or 0.35%. Certain populations are known to have a higher prevalence of founder mutations, including, but not limited to, French Canadians, Icelanders, African Americans, and Ashkenazi Jews.
Терминология
Генри Т. Линч, профессор медицины в Медицинском центре Университета Крейтона, охарактеризовал этот синдром в 1966 году. В более ранних работах он описывал это заболевание как "семейный синдром рака". Термин "синдром Линча" был предложен в 1984 году другими авторами, а Линч назвал это состояние HNPCC в 1985 году. После этого оба термина использовались как взаимозаменяемые, пока дальнейшие успехи в понимании генетики заболевания не привели к тому, что термин HNPCC вышел из употребления. Некоторые авторы резервируют термин "синдром Линча" для случаев с установленным дефектом системы репарации ДНК, а термин "семейный колоректальный рак типа X" используют, когда выполняются Амстердамские критерии, но дефект системы репарации ДНК не выявлен. Предполагается, что в семьях "типа X" общая заболеваемость раком и риск развития неколоректальных злокачественных новообразований ниже, чем в семьях с подтвержденным дефицитом системы репарации ДНК. Примерно у 35% пациентов, соответствующих Амстердамским критериям, не обнаруживается мутаций в генах системы репарации ДНК. Ситуацию осложняет наличие альтернативного набора критериев, известных как "Руководство Бетесда".
Henry T. Lynch, Professor of Medicine at Creighton University Medical Center, characterized the syndrome in 1966. In his earlier work, he described the disease entity as "cancer family syndrome." The term "Lynch syndrome" was coined in 1984 by other authors; Lynch named the condition HNPCC in 1985. Since then the two terms have been used interchangeably, until later advances in the understanding of the genetics of the disease led to the term HNPCC falling out of favor. Other sources reserve the term "Lynch syndrome" when there is a known DNA mismatch repair defect, and use the term "familial colorectal cancer type X" when the Amsterdam criteria are met but there is no known DNA mismatch repair defect. The putative "type X" families appear to have a lower overall incidence of cancer and lower risk for non colorectal cancers than families with documented DNA mismatch repair deficiency. About 35% of people who meet Amsterdam criteria do not have a DNA mismatch repair gene mutation. Complicating matters is the presence of an alternative set of criteria, known as the "Bethesda Guidelines."
Общество
Есть ряд некоммерческих организаций, предоставляющих информацию и поддержку, включая Lynch Syndrome International, AliveAndKickn, Lynch Syndrome UK и Bowel Cancer UK. В США Национальный день повышения осведомленности о синдроме Линча отмечается 22 марта.
There are a number of non profit organisations providing information and support, including Lynch Syndrome International, AliveAndKickn, Lynch Syndrome UK and Bowel Cancer UK. In the US, National Lynch Syndrome Awareness Day is March 22.