What is Lynch syndrome, its core genes, and the cancer spectrum involved?

• A. Lynch syndrome is hereditary nonpolyposis colorectal cancer caused by germline mutations in MLH1, MSH2, MSH6, PMS2, or EPCAM deletions; it increases colorectal, endometrial, ovarian, gastric, and other cancers.
• B. Lynch syndrome is a BRCA-related syndrome; breast and ovarian cancers are the main risk.
• C. Lynch syndrome is caused by APC mutations; colorectal cancer risk only.
• D. Lynch syndrome is not hereditary; somatic mosaic.

Answer: (A)

Lynch syndrome is an inherited cancer predisposition caused by germline mutations in DNA mismatch repair genes, which leads to microsatellite instability and accumulation of replication errors. The genes involved are MLH1, MSH2, MSH6, and PMS2, with deletions in EPCAM that can also cause Lynch syndrome by silencing MSH2. The cancer spectrum goes beyond colorectal cancer and includes a high risk for endometrial and ovarian cancers, as well as gastric, small bowel, pancreatic, urinary tract (renal pelvis and ureter), biliary tract cancers, and sometimes certain brain and skin tumors. It is inherited in an autosomal dominant pattern, and testing typically starts with tumor MSI/IHC screening followed by germline testing to confirm and guide family cascade testing.