HNPCC

Hereditary nonpolyposis colorectal cancer (HNPCC), now more commonly called Lynch syndrome, is an inherited cancer predisposition. It is caused by germline variants in DNA mismatch repair (MMR) genes, most often MLH1, MSH2, MSH6, or PMS2. In some families, deletions in EPCAM lead to MSH2 inactivation. Tumors in Lynch syndrome frequently show microsatellite instability (MSI) or loss of MMR protein expression.

The syndrome markedly increases the risk of colorectal cancer, often at a younger age than sporadic cases. Cancers may arise in the proximal colon. There is also a high risk of extracolonic cancers, particularly endometrial cancer in women, as well as ovarian, stomach, small intestine, urinary tract, biliary tract, and other cancers, with risks varying by gene.

Diagnosis combines clinical criteria with tumor testing and genetic confirmation. Tumors are screened for MSI or MMR deficiency; immunohistochemistry can show loss of specific MMR proteins. If abnormal, germline testing identifies pathogenic variants. Cascade testing of at-risk relatives is recommended.

Management focuses on surveillance and risk-reduction. Colorectal cancer screening commonly starts in early adulthood and is repeated every 1–2 years. For women, gynecologic cancer risk is discussed, with options such as risk-reducing surgery after childbearing in some cases. Evidence from trials supports potential use of low-dose aspirin for cancer risk reduction in Lynch syndrome in some individuals. Genetic counseling and multidisciplinary follow-up are important.