A germline mutation at the extreme 3 ' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor

Desmoid tumors arise sporadically or as part of the extraintestinal manifes tations of familial adenomatous polyposis (FAP). In FAP, two distinct clini cal presentations of the desmoid phenotype are seen: 1) one or a few desmoi d tumors present predominantly in the abdominal wall or the abdomen; 2) a f lorid proliferation of tumors early in life, mostly near the axial skeleton or extremities. These different phenotypes have been associated with diffe rent sites of germline mutations in the adenomatous polyposis coli gene (AP C gene). We present a large, French-Canadian kindred with a florid desmoid tumor phe notype caused by a germline mutation at codon 2643-2644 of the APC gene. Th e phenotype was characterized by the early onset of multiple tumors, arisin g near the axial skeleton and in proximal extremities. The penetrance of de smoid tumors was near 100% in this kindred. However, the expression of the disease was variable amongst the different affected relatives. Many gene ca rriers had cutaneous cysts. Polyposis of the colon was rarely observed in t he affected individuals and we did not document upper gastro-intestinal pol yps. The mutant APC allele did not express a stable truncated protein in vi vo. Molecular analysis of the proband's tumor DNA revealed a somatic inacti vating mutation of the wild-type allele. Immunohistochemistry on the tumor also demonstrated elevated levels of beta-catenin. The present study demonstrates that this extreme 3' APC mutation is associa ted with a severely penetrant desmoid phenotype and attenuated polyposis co li. It also suggests the involvement of the beta-catenin pathway in the dev elopment of desmoid tumors in FAP. The natural history of the disease is va riable between individuals, and surgical interventions have to be timed app ropriately due to the frequent recurrences.