DNA mismatch repair genes and colorectal cancer

Positional cloning and linkage analysis have shown that inactivation of one of the mismatch repair genes (hMLH1, hMSH2, hPMS1, hPMS2, GTBP/hMSH6) is r esponsible for the microsatellite instability or replication error (RER+) s een in more than 90% of hereditary nonpolyposis colorectal cancers (HNPCC) and 15% of sporadic RER+ colorectal cancers. In HNPCC, a germline mutation (usually in hMLH1 or hMSH2) is accompanied by one further event (usually al lelic loss) to inactivate a mismatch repair gene. In contrast, somatic muta tions in the mismatch repair genes are not frequently found in sporadic RER + colorectal cancers. Hypermethylation of the hMLH1 promoter region has rec ently been described, and this epigenetic change is the predominant cause o f inactivation of mismatch repair genes in sporadic RER+ colorectal and oth er cancers. Inactivation of a mismatch repair gene may occur early (before inactivation of the APC gene), and produce a raised mutation rate in a prop ortion of HNPCC patients, and these cancers will follow a different pathway to other RER+ cancers. However, it is likely that selection for escape fro m apoptosis is the most important feature in the evolution of an RER+ cance r.