TISSUES OF MSH2-DEFICIENT MICE DEMONSTRATE HYPERMUTABILITY ON EXPOSURE TO A DNA METHYLATING AGENT

The mutational response of mismatch repair-deficient animals to the al kylating agent N-methyl-N-nitrosourea was evaluated by using a transge nic lad reporter system, Although the mutations detected in MSH2 heter ozygotes were similar to those of controls, MSH2(-/-) animals demonstr ated striking increases in mutation frequency in response to this agen t. G:C to A:T transitions at GpG sites, as opposed to CpG sites, domin ated the mutational spectrum of both MSH2(+/+) and MSH2(-/-) N-methyl- N-nitrosourea-treated animals, Extrapolating to humans with hereditary non-polyposis colorectal cancer, the results suggest that MSH2 hetero zygotes are unlikely to be at increased risk of mutation, even when ex posed to potent DNA methylating agents, In contrast, mismatch repair-d eficient cells spontaneously arising within individuals with hereditar y nonpolyposis colorectal cancer would likely exhibit hypermutability in response to such mutagens, an outcome predicted to accelerate the p ace of tumorigenesis.