Lynch syndrome, caused by a germline mutation in a mismatch repair gene and associated with tumors exhibiting microsatellite instability (MSI), is characterized by an increased risk of 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 mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). MLH1 and MSH2 germline mutations account for approximately 90% of mutations in families with Lynch syndrome; MSH6 mutations in about 7%-10%; and PMS2 mutations 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. 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 mutation. 2. Molecular genetic testing of the tumor for methylation and somatic BRAF mutations to help identify those tumors more likely to be sporadic than hereditary. 3. Molecular genetic testing of the MMR genes to identify a germline mutation when findings are consistent with Lynch syndrome.
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 mutation 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 mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known. Requests for prenatal testing for typically adult-onset conditions which (like Lynch syndrome) have treatment available are not common.