Hereditary Nonpolyposis Colorectal Cancer

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer (CRC). The disease carries a >80% lifetime risk of CRC (mean age at diagnosis being 46 years). The CRCs that arise in HNPCC are usually right-sided and associated with synchronous and metachronous tumors. HNPCC is also associated with a high risk of extracolonic cancers, predominantly endometrial cancer. Predisposition to cancer in HNPCC has been attributed to mutations in mismatch repair (MMR) genes, over 95% of the identified mutations in HNPCC being in hMSH2 , hMLH1 , and hMSH6 . The abnormal MMR genes lead to instabilities in nucleotide repeat sequences (microsatellites) within the genome (MSI, microsatellite instability) that may lead to tumorigenesis and concerning pathologic features but improved clinical outcomes when compared with sporadic CRCs without MSI. Mutations in MMR genes are also associated with a host of other extraintestinal cancers. Each individual MMR gene has its own genotype-phenotype pattern of expression that can vary from individual to individual. As a result, this genetic information can be used to direct surveillance of affected and at-risk family members. Once the clinical criteria for HNPCC have been met and/or a gene mutation confirmed, affected patients show improved survival with cancer screenings every 1 to 2 years starting before age 25 years. Prophylactic colectomy for asymptomatic gene mutation carriers and the extent of colectomy when polyps or cancer arise in HNPCC remain the subject of debate. This issue will discuss our current understanding of the genetics of HNPCC, the various phenotypic expressions, genetic testing, surveillance, and current recommendations of management of this familial cancer syndrome.