Mlh1 deficiency enhances several phenotypes of Apc(Min/+) mice

Defects in APC and DNA mismatch repair genes are associated with a strong p redisposition to colon cancer in humans, and numerous mouse strains with mu tations in these genes have been generated. In this report we describe the phenotype of Min/+ Mlh1(-/-) mice. We find that these doubly mutant mice de velop more than three times the number of intestinal adenomas compared to M in/+ Mlh1(+/+) or (+/-) mice but that these tumors do not show advanced pro gression in terms of tumor size or histological appearance. Full length Apc protein was not detected in the tumor cells from Min/+ Mlh1(-/-) mice. Mol ecular analyses indicated that in many tumors from Min/+ Mlh1(-/-) mice, Ap c was inactivated by intragenic mutation. Mlh1 deficiency in Min/+ mice als o led to an increase in cystic intestinal crypt multiplicity as well as enh ancing desmoid tumorigenesis and epidermoid cyst development. Thus, Mlh1 de ficiency influences the somatic events involved in the development of most of the phenotypes associated with the Min mutation.