Related Gene(s): MLH1, MSH2, MSH6, EPCAM, PMS2
Lynch syndrome is an autosomal dominant hereditary cancer syndrome that causes increased risk for several types of cancer, primarily colorectal and uterine (also known as endometrial) cancer. Other associated cancers include stomach, ovarian, small bowel, hepatobiliary tract, upper urinary tract, brain, and pancreatic cancers, and sebaceous neoplasms.
Lynch syndrome is caused by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2, and EPCAM. An estimated 90% of mutations are found in the MLH1 and MSH2 genes, 7-10% are in the MSH6 gene, and less than 5% are detected in the PMS2 gene. More recent data suggests that mutations in MSH6 and PMS2 may result in a milder form of Lynch syndrome with an older age of onset and/or lower cancer risks than MLH1 and MSH2. EPCAM (also known as TACSTD1) is the epithelial cell adhesion molecule located upstream of MSH2. Gross deletions disrupting the 3’ end of EPCAM lead to inactivation of the adjacent MSH2 gene through methylation induction of its promoter. Germline deletions encompassing this region have been reported in 19-30% of individuals with microsatellite instability (MSI) and absence of the MSH2 protein in their tumors identified by immunohistochemistry (IHC).
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