Genetic basis of hereditary nonpolyposis colorectal carcinoma (HNPCC).

Hereditary nonpolyposis colorectal cancer (HNPCC) represents the most common form of genetic predisposition to colon cancer. Even in kindreds with several affected members it is, however, difficult to rule out chance clustering and other nonhereditary factors since colon cancer is so common in the general population. Similarly, it is impossible to distinguish individual patients with HNPCC from sporadic cases on clinical grounds since neither have polyposis or other specific physical signs. The localization of an HNPCC gene on chromosome 2 in May 1993 provided formal proof that HNPCC is a single gene (Mendelian) disorder. Instability at short tandem repeat sequences (microsatellites) was found to characterize HNPCC tumours. Positional and functional cloning strategies resulted in the identification of the HNPCC gene in December 1993. Interspecies homology suggests that the gene, hMSH2, functions in DNA mismatch repair. These findings provide a theoretical basis as well as practical tools to detect susceptibility to HNPCC cancers.