Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice

MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer suscept ibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC), We gene rated mice carrying a null mutation in the Mlh1 gene. We showed that mice h eterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, Lymphomas, and a number of other tumor types, We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different meth ods and showed that the GI tumors in Mlh1 mice express little or no adenoma tous polyposis coli protein, When an Ape gene mutation was bred into the Ml h1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Ape allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and t hat the mechanisms of tumor development in the GI tract of these mice invol ve loss of Apc gene function in a manner very similar to that seen in the G I tumors of HNPCC.