Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent

The mutational response of mismatch repair-deficient animals to the alkylating agent N-methyl-N-nitrosourea was evaluated by using a transgenic lad reporter system, Although the mutations detected in MSH2 heterozygotes were similar to those of controls, MSH2(-/-) animals demonstrated striking increases in mutation frequency in response to this agent. G:C to A:T transitions at GpG sites, as opposed to CpG sites, dominated 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 heterozygotes are unlikely to be at increased risk of mutation, even when exposed to potent DNA methylating agents, In contrast, mismatch repair-deficient cells spontaneously arising within individuals with hereditary nonpolyposis colorectal cancer would likely exhibit hypermutability in response to such mutagens, an outcome predicted to accelerate the pace of tumorigenesis.