TUMOR SUSCEPTIBILITY AND SPONTANEOUS MUTATION IN MICE DEFICIENT IN MLH1, PMS1 AND PMS2 DNA MISMATCH REPAIR

Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer (HNPCC; refs 1-5). An im portant role for DNA replication errors in colorectal tumorigenesis ha s been suggested by the finding of frequent alterations in the length of specific mononucleotide tracts within genes controlling cell growth , including TGF-beta receptor type II (ref. 6), BAX (ref. 7) and APC ( ref. 8). A broader role for MMR deficiency in human tumorigenesis is i mplicated by microsatellite instability in a fraction of sporadic tumo urs, including gastric, endometrial and colorectal malignancies(9). To better define the role of individual MMR genes in cancer susceptibili ty and MMR functions, we have generated mice deficient for the murine homologues of the human genes MLH1, PMS1 and PMS2. Surprisingly, we fi nd that these mice show different tumour susceptibilities, most notabl y, to intestinal adenomas and adenocarcinomas, and different mutationa l spectra. Our results suggest that a general increase in replication errors may not be sufficient for intestinal tumour formation and that these genes share overlapping, but not identical functions.