A TARGETED CHAIN-TERMINATION MUTATION IN THE MOUSE APC GENE RESULTS IN MULTIPLE INTESTINAL TUMORS

Germ line mutations in the human adenomatous polyposis coli (APC) gene result in familial adenomatous polyposis, an autosomal dominant disor der characterized by the early onset of multiple adenomatous polyps in the large bowel with a high likelihood of developing colorectal carci nomas. To understand the role of APC in intestinal tumor formation, we have introduced a chain-termination mutation in the 15th exon of the mouse Apc gene and employed it to modify the endogenous gene by homolo gous recombination in embryonic stem cells. Mice which are heterozygou s for the Apc gene modification progressively develop intestinal tumor s in a manner that is similar to that observed in patients with famili al adenomatous polyposis and in mice which carry a mutation called mul tiple intestinal neoplasia (Min). Our results indicate that the Apc ge ne modification is a critical event in the initiation of intestinal tu mor formation and results in an autosomal dominant predisposition towa rd development of spontaneous colonic and intestinal tumors in mice.