LynchSyndrom

Lynch syndrome is a hereditary cancer syndrome caused by germline variants in DNA mismatch repair genes. It is inherited in an autosomal dominant manner and markedly increases lifetime risk of several cancers, most notably colorectal and endometrial cancer, but also ovarian, stomach, small intestine, biliary tract, urinary tract, brain tumors, and some skin tumors.

Major genes include MLH1, MSH2, MSH6, and PMS2, with EPCAM deletions altering MSH2 expression in some families. Penetrance and cancer risks vary by gene and family, but colorectal cancer risk is commonly high and endometrial cancer risk substantial. The syndrome arises from defective DNA mismatch repair, leading to microsatellite instability in tumors.

Most Lynch-associated tumors show microsatellite instability and may appear at younger ages than sporadic cancers. The cancer spectrum is broad and includes colorectal and endometrial cancers as well as ovarian, stomach, small bowel, pancreatic, hepatobiliary, urinary tract cancers, brain tumors, and certain skin tumors (in the Muir-Torre variant).

Diagnosis combines family history assessment and tumor testing. Amsterdam criteria and revised Bethesda guidelines identify candidates for germline testing. Tumors are tested for MSI and MMR protein loss by immunohistochemistry, and germline sequencing confirms pathogenic variants. Distinguishing Lynch syndrome from sporadic MSI due to MLH1 promoter methylation is important for management.

Management emphasizes surveillance and risk reduction. Colorectal screening with colonoscopy every 1–2 years typically starts at 20–25 years. Gynecologic risk management may include annual endometrial assessment and discussion of risk-reducing surgery after childbearing. Aspirin chemoprevention has been studied, and relatives should be offered predictive testing to guide surveillance and treatment decisions. In some cancers, MSI status informs immunotherapy options.