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


Corresponding author: Dr Jean Couture, Mount Sinai Hospital, 600 University Ave, Suite 1225, Toronto, Ontario, Canada M5G 1X5. Tel: +1 416 586 5360; fax: +1 416 586 8392; e-mail: jcouture@mtsinai.on.ca


Desmoid tumors arise sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis (FAP). In FAP, two distinct clinical presentations of the desmoid phenotype are seen: 1) one or a few desmoid tumors present predominantly in the abdominal wall or the abdomen; 2) a florid proliferation of tumors early in life, mostly near the axial skeleton or extremities. These different phenotypes have been associated with different sites of germline mutations in the adenomatous polyposis coli gene (APC gene).
We present a large, French-Canadian kindred with a florid desmoid tumor phenotype caused by a germline mutation at codon 2643-2644 of the APC gene. The phenotype was characterized by the early onset of multiple tumors, arising near the axial skeleton and in proximal extremities. The penetrance of desmoid tumors was near 100% in this kindred. However, the expression of the disease was variable amongst the different affected relatives. Many gene carriers had cutaneous cysts. Polyposis of the colon was rarely observed in the affected individuals and we did not document upper gastro-intestinal polyps. The mutant APC allele did not express a stable truncated protein in vivo. Molecular analysis of the proband's tumor DNA revealed a somatic inactivating 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 associated with a severely penetrant desmoid phenotype and attenuated polyposis coli. It also suggests the involvement of the beta-catenin pathway in the development of desmoid tumors in FAP. The natural history of the disease is variable between individuals, and surgical interventions have to be timed appropriately due to the frequent recurrences.