Mutations in DNA mismatch repair (MMR) genes are associated with increased genomic instability and susceptibility to cancer. Mice rendered deficient in either Mlh1 or Pms2 as a result of gene targeting are prone to tumorigenesis, particularly, lymphomas. In addition, although Mlh1−/− mice also develop small intestinal adenomas and adenocarcinomas, Pms2−/− animals remain free of such tumors. To establish whether this phenotypic dichotomy might be associated with a quantitative and/or qualitative difference in genomic instability in these mice, we determined small intestinal epithelial cell DNA mutant frequency and mutation spectrum using a transgenic λ-phage lacI reporter system. Mutant frequencies obtained from both Mlh1−/− and Pms2−/− mice revealed elevations of 18- and 13-fold, respectively, as compared to their wild-type littermates. Interestingly, we found that C : G→T : A transitions were significantly elevated in Mlh1−/− mice, accounting in large measure for the 1.5-fold lacI mutant frequency increase seen in these animals. We hypothesize that the increased level of C : G→T : A mutations may explain, in part, why Mlh1−/− mice, but not Pms2−/− mice, develop small intestinal tumors. Furthermore, the difference in the lacI mutational spectrum of Mlh1−/− and Pms2−/− mice suggests that other MutL-like heterodimers may play important roles in the repair of G : T mispairs arising within murine small intestinal epithelial cells.
