APC and its modifiers in colon cancer

Abstract

Colon cancer closely follows the paradigm of a single "gatekeeper gene." Mutations inactivating the APC (adenomatous polyposis coli) gene are found in approximately 80% of all human 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 of the 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 of genetic modifiers of the Apc-mutant phenotypes, connecting the central role of Apc in colon carcinogenesis to the myriad factors that ultimately determine the course of the disease.

Figure 1. Organization of the mouse, rat, and human chromosomes bearing the APC/Apc and Mom7 orthologs

A) The Apc locus of the mouse lies on a telocentric chromosome, in contrast to its orthologs in the rat and human, each of which lies on a metacentric chromosome. A metacentric character enables a facile discrimination between whole chromosome loss versus somatic recombination. B) The APC/Apc locus of the mouse is linked to the Mom7 locus on Chr 18, while the orthologs of these two loci are not linked in the rat and human karyotypes.

Figure 2. The structure of the Apc protein

Arrows indicate orthologous locations of mouse model mutations and the two most common FAP mutation sites. The color bar below indicates the genotype-phenotype correlation of sites of protein truncation to disease severity. The data used to generate the color bar can be found at http://www.mcardle.wisc.edu/dove/Data/Apc.htm.