Southwestern internal medicine conference: hereditary predisposition to colorectal cancer: new insights.

Hereditary predisposition to colorectal cancer assumes two well-defined forms: familial adenomatous polyposis and hereditary nonpolyposis colon cancer. These tumors segregate as autosomal dominant conditions whose penetrance increases with age; cancer is expected to develop ultimately in as much as 50% of the offspring of affected individuals. These traits account for less than 1% and approximately 5% of all colorectal cancer, respectively. In addition, first-degree relatives of patients with common (sporadic) colorectal neoplasia are at increased risk of colorectal cancer. This relative risk averages approximately twofold but is significantly higher for relatives of younger patients (age at diagnosis, < 55 years). Familial adenomatous polyposis and a major subset of hereditary nonpolyposis colon cancer are due to loss-of-function germline mutations of genes located on chromosomes 5q and 2p, respectively. Both of these genes have been cloned recently. The gene affected in familial polyposis, APC, encodes a protein of unknown function that normally is found on the surface of maturing cells in the upper colonic crypts. The relevant gene in many hereditary nonpolyposis colon cancer kindreds is hMSH2. This gene encodes the human homologue of a bacterial protein MutS, which is part of a system known to repair base mismatches in newly replicated DNA. Loss of hMSH2 function may explain the strikingly erroneous replication of short DNA repeats (microsatellites) in colon tumors from patients with hereditary nonpolyposis colon cancer. Because this error-prone replication is found in approximately 13% of nonfamilial colon cancers, defective mismatch repair may contribute to the development of both hereditary and sporadic colon neoplasia. Molecular genetic assays to detect mutated alleles of these genes will facilitate presymptomatic identification of carriers in families with familial polyposis and hereditary nonpolyposis colon cancer. Current recommendations for surveillance of family members are presented in the light of the new genetic understanding of these diseases.