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Lynch Syndrome.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
2004 Feb 5 [updated 2014 May 22].



Lynch syndrome, caused by a germline pathogenic variant in a mismatch repair gene and associated with tumors exhibiting microsatellite instability (MSI), is characterized by an increased risk for colon cancer and cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following life time risks for cancer are seen: 52%-82% for colorectal cancer (mean age at diagnosis 44-61 years); 25%-60% for endometrial cancer in women (mean age at diagnosis 48-62 years); 6% to 13% for gastric cancer (mean age at diagnosis 56 years); and 4%-12% for ovarian cancer (mean age at diagnosis 42.5 years; approximately 30% are diagnosed before age 40 years). The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.


The diagnosis of Lynch syndrome can be made on the basis of family history in those families meeting the Amsterdam criteria who have tumor microsatellite instability (MSI) or on the basis of molecular genetic testing in an individual or family with a germline pathogenic variant in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). MLH1 and MSH2 germline pathogenic variants account for approximately 90% of pathogenic variants in families with Lynch syndrome; MSH6 pathogenic variants in about 7%-10%; and PMS2 pathogenic variants in fewer than 5%. Germline deletions in EPCAM (not a mismatch repair gene) inactivate MSH2 in about 1% of individuals with Lynch syndrome. Genetic testing for Lynch syndrome is ideally performed in a stepwise manner: 1. Tumor testing: a. Evaluation of tumor tissue for MSI through molecular MSI testing and/or immunohistochemistry (IHC) of the four MMR proteins. The presence of MSI in the tumor alone is not sufficient to diagnosis Lynch syndrome because 10%-15% of sporadic colorectal cancers exhibit MSI. IHC testing helps identify the MMR gene that most likely harbors a germline pathogenic variant. b. Molecular genetic testing of the tumor for MLH1 methylation and somatic BRAF pathogenic variant to help identify those tumors more likely to be sporadic than hereditary. 2. Molecular genetic testing of the MMR genes to identify a germline pathogenic variant when findings are consistent with Lynch syndrome.


Treatment of manifestations: For colon cancer, full colectomy with ileorectal anastomosis is recommended. Prevention of primary manifestations: Prophylactic removal of the colon prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because routine colonoscopy is an effective preventive measure. Prophylactic removal of the uterus and ovaries (prior to the development of cancer) can be considered after childbearing is completed. Surveillance: Colonoscopy with removal of precancerous polyps every one to two years beginning between ages 20 and 25 years or two to five years before the earliest age of diagnosis in the family, whichever is earlier. The efficacy of surveillance for cancer of the endometrium, ovary, stomach, duodenum, and urinary tract is unknown. Agents/circumstances to avoid: Cigarette smoking. Evaluation of relatives at risk: Genetic testing for Lynch syndrome is generally not recommended for at-risk individuals younger than age 18 years; however, because it is recommended that screening begin ten years before the earliest age of cancer onset in a family, molecular genetic testing and screening colonoscopy may need to begin before age 18 years in some families.


Lynch syndrome is inherited in an autosomal dominant manner. The majority of individuals diagnosed with Lynch syndrome have inherited the condition from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction as a result of screening or prophylactic surgery, or early death, not all individuals with a pathogenic variant in one of the genes associated with Lynch syndrome have a parent who had cancer. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known. Requests for prenatal testing for typically adult-onset conditions which (like Lynch syndrome) have treatment available are not common.

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