Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor)

Aggressive fibromatosis (also called desmoid tumor) occurs as a sporadic le sion or as part of Familial Adenomatous Polyposis, which is caused by germ line mutations in the Adenomatous polyposis Coli (APC) gene. APC is involve d in the regulation of the cellular level of beta-catenin, which is a media tor in Wnt signaling, Mutational analysis of the beta-catenin and APC genes was performed in 42 sporadic aggressive fibromatoses. Nine tumors had muta tions in APC, and 22 had a point mutation in beta-catenin at either codon 4 5 or codon 41 (producing a stabilized beta-catenin protein product). Immuno histochemistry showed an elevated beta-catenin protein level in all tumors, regardless of mutational status. Beta-catenin localized to the nucleus, an d was not tyrosine phosphorylated in the six tumors in which this was teste d. The demonstration of mutations in two mediators in the Wnt-APC-beta-cate nin pathway implicates beta-catenin stabilization as the key factor in the pathogenesis of aggressive fibromatosis. This is the first demonstration of somatic beta-catenin mutations in a locally invasive, but non metastatic l esion composed of spindle cells, illustrating the importance of beta-cateni n stabilization in a variety of cell types and neoplastic processes. Moreov er, this tumor has one of the highest reported frequencies of beta-catenin mutations of any tumor type.