MISMATCH REPAIR DEFECTS IN HUMAN CARCINOGENESIS

Mismatch repair defects are carcinogenic. This conclusion comes some 8 0 years after the original description of a type of familial colorecta l cancer in which mismatch repair defects are involved, and from decad es of dedicated basic science research into fundamental mechanisms cel ls use to repair their DNA. Mismatch repair (MMR) was described first in bacteria, later in yeast and finally in higher eukaryotes. In bacte ria, one of its roles is the rapid repair of replicative errors thereb y providing the genome with a 100-1000-fold level of protection agains t mutation. It also guards the genome by preventing recombination betw een non-homologous regions of DNA, The information gained from bacteri a suddenly became relevant to human neoplasia in 1993 when the RER phe notype of microsatellite instability was discovered in human cancers a nd was rapidly shown to be due to defects in mismatch repair. Evidence supporting the role of MMR defects in carcinogenesis comes from a var iety of independent sources including: (i) theoretical considerations of the requirement for a mutator phenotype as a step in multistage car cinogenesis; (ii) discovering that MMR defects cause a 'mutator phenot ype' destabilizing endogenous expressed genes including those integral to carcinogenesis; (iii) finding MMR defects in the germline of HNPCC kindred members; (iv) finding that such defects behave as classic tum or suppressor genes in both familial and sporadic colorectal cancers; (v) discovering that MMR 'knockout' mice have an increased incidence o f tumors; and (vi) discovering that genetic complementation of MMR def ective cells stabilizes the MMR deficiency-associated microsatellite i nstability, Models of carcinogenesis now must integrate the concepts o f a MMR defect induced mutator phenotype (Loeb) with the concepts of m ultistep colon carcinogenesis (Fearon and Vogelstein) and clonal heter ogeneity/selection (Nowell).