Deficient DNA mismatch repair: a common etiologic factor for colon cancer

Hereditary non-polyposis colon cancer (HNPCC), the most common form of here ditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR), Five, possibly six, human MMR genes have been identified that, when mutated in the germline, cause susceptibility to this syndrome. To date, more than 300 different predisposing mutations are known, mainly affecting the MMR g enes MLH1 (similar to 50%), MSH2 (similar to 40%) and MSH6 (similar to 10%) , Genetically predisposed individuals carry a defective copy of an MMR gene in every cell, Somatic inactivation of the remaining wild-type copy in a t arget tissue, typically colon, gives rise to a profound repair defect, prog ressive accumulation of mutations and cancer, Instability at short tandem r epeat sequences, microsatellites, is a typical manifestation of MMR deficie ncy and apart from HNPCC tumors, occurs in similar to 15% of sporadic colon and other tumors. The majority of the latter cases are attributable to one particular MMR gene, MLH1, and unlike HNPCC, an epigenetic rather than a g enetic mechanism plays an important role in the inactivation of this gene. The present review provides an update of the genetics of HNPCC and more gen erally, of cancer development driven by deficient MMR, Recent discoveries s uggest that apart from post-replication repair, MMR proteins have several o ther functions that are highly relevant to carcinogenesis, Knowledge of the complex interplay between the MMR system and other cellular pathways allow s us to better understand the phenotypic manifestations of HNPCC and other cancers with deficient MMR.