Inactivation of germline mutant APC alleles by attenuated somatic mutations: A molecular genetic mechanism for attenuated familial adenomatous polyposis

Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in familial adenomatous polyposis (FAP). Patients with FAP typ ically develop hundreds to thousands of benign colorectal tumors and early- onset colorectal cancer. A subset of germline APC mutations results in an a ttenuated FAP (AFAP) phenotype, in which patients develop fewer tumors and develop them at an older age. Although a genotype-phenotype correlation bet ween the locations of APC germline mutations and the development of AFAP ha s been well documented, the mechanism for AFAP has not been well defined. W e investigated the mechanism for AFAP in patients carrying a mutant APC all ele (APC(AS9)) that has a mutation in the alternatively spliced region of e xon 9. APC(AS9) was found to down-regulate beta-catenin-regulated transcrip tion, the major tumor-suppressor function of APC, as did the wildtype APC. Mutation analysis showed that both APC(AS9) and the wild-type APC alleles w ere somatically mutated in most colorectal tumors from these patients. Func tional analysis showed that 4666insA, a common somatic mutation in APC(AS9) in these tumors, did not inactivate the wild-type APC. Our results indicat e that carriers of APC(AS9) develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is nece ssary for colorectal tumorigenesis. However, these patients develop colorec tal tumors more frequently than does the general population because APC(AS9 ) is inactivated by mutations that do not inactivate the wild-type APC.