APC and its modifiers in colon cancer

Colon cancer closely follows the paradigm of a single "gatekeeper gene". Mutations inactivating the APC (adenomatous polyposis coli) gene are found in -80% of allhuman colon tumors and heterozygosity for such mutations produces an autosomal dominant colon cancer predisposition in humans and in murine models. However, this tight association between a single genotype and phenotype belies a complex association of genetic and epigenetic factors that together generate the broad phenotypic spectrum ofboth familial and sporadic colon cancers. In this Chapter,we give a general overview ofthe structure, function and outstanding issues concerning the role of Apc in human and experimental colon cancer. The availability of increasingly close models for human colon cancer in genetically tractable animal species enables the discovery and eventual molecular identification ofgenetic modifiers ofthe Ape-mutantphenotypes, connecting the central role of Ape in colon carcinogenesis to the myriad factors that ultimately determine the course of the disease.