APC mutations in sporadic colorectal tumors: A mutational "hotspot" and interdependence of the "two hits"

Although APC mutations occur at a high frequency in colorectal cancers, few studies have performed a comprehensive analysis by screening the whole gen e for mutations and assessing allelic loss. APC seems to act as a tumor-sup pressor gene in a "nonclassical" fashion: data from familial adenomatous po lyposis (FAP) show that the site of the germ-line mutation determines the t ype of "second hit" in FAP tumors, and simple protein inactivation is selec ted weakly, if at all. In this study, we screened the entire coding region of APC for mutations and assessed allelic loss in a set of 41 colorectal ca ncer cell lines. Of 41 cancers, 32 (83%) showed evidence of APC mutation an d/or allelic loss. We identified several APC mutations and found a "hotspot " for somatic mutation in sporadic colorectal tumors at codon 1,554. Our re sults suggest that APC mutations occur in the great majority of colorectal cancers, the exceptions almost all being RER+ tumors, which may substitute for altered APC function by mutations in beta-catenin and/or at other loci. When combined with previously published data, our results show that there is interdependence of the "two hits" at APC in sporadic colorectal tumors a s well as in FAP. APC mutations in the "mutation cluster region," especiall y those close to codon 1,300, are associated with allelic loss, whereas tum ors with mutations outside this region tend to harbor truncating mutations. The causes of this phenomenon are probably selection far retained N-termin al and lost C-terminal APC functions, effects on beta-catenin levels, and A PC protein stability.