Lynch syndrome

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is one of the most common hereditary cancer predisposition syndromes. It is caused by germline pathogenic variants in DNA mismatch repair (MMR) genes — MLH1, MSH2, MSH6, PMS2 — or by deletions in the EPCAM gene that lead to epigenetic silencing of MSH2. These genes are essential for correcting errors that occur during DNA replication, and when they are dysfunctional, cells accumulate mutations at an accelerated rate, a phenomenon known as microsatellite instability (MSI). Lynch syndrome primarily increases the risk of colorectal cancer, with a lifetime risk estimated at 40–80% depending on the specific gene involved. It also significantly raises the risk of endometrial (uterine) cancer in women (40–60% lifetime risk), as well as cancers of the ovaries, stomach, small intestine, urinary tract (renal pelvis and ureter), brain, hepatobiliary tract, and skin (sebaceous neoplasms). Colorectal cancers in Lynch syndrome tend to occur at younger ages than sporadic cases, often before age 50, and are more frequently located in the proximal (right-sided) colon. Individuals may develop multiple primary cancers over their lifetime. Management of Lynch syndrome centers on intensive cancer surveillance and risk reduction. Colonoscopy is recommended every 1–2 years beginning at age 20–25 (or earlier depending on family history), which has been shown to significantly reduce colorectal cancer incidence and mortality. For women, gynecologic surveillance and consideration of risk-reducing hysterectomy and bilateral salpingo-oophorectomy after completion of childbearing are recommended. Aspirin chemoprevention has shown promise in reducing cancer risk in Lynch syndrome carriers, supported by the CAPP2 trial. Immunotherapy with immune checkpoint inhibitors (such as pembrolizumab and nivolumab) has demonstrated remarkable efficacy in treating MSI-high/MMR-deficient cancers arising in Lynch syndrome, representing a major advance in the treatment landscape. Genetic counseling and cascade testing of at-risk family members are essential components of care.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

Common questions about Lynch syndrome