INCREASED BETA-CATENIN PROTEIN AND SOMATIC APC MUTATIONS IN SPORADIC AGGRESSIVE FIBROMATOSES (DESMOID TUMORS)

Sporadic aggressive fibromatosis (also called desmoid tumor) is a mono clonal proliferation of spindle (fibrocyte-like) cells that is locally invasive but does not metastasize. A similarity to abdominal fibromat oses (desmoids) in familial adenomatous polyposis and a cytogenetic st udy showing partial deletion of 5q in a subset of aggressive fibromato ses suggests that the adenomatous polyposis coli (APC) gene plays a ro le in its pathogenesis. APC helps regulate the cellular level of beta- catenin, which is a downstream mediator in Wnt (Wingless) signaling, b eta-catenin has a nuclear function (binds transcription factors) and a cell mem brane function (is a component of epithelial cell adherens j unctions), Six cases of aggressive fibromatosis of the extremities fro m patients without familial adenomatous polyposis, or a family history of colon cancer, were studied. Immunohistochemistry, using carboxy an d amino terminus antibodies to APC, and DNA sequencing showed that thr ee of the six contained an APC-truncating mutation, whereas normal tis sues did not contain a mutation. Western blot and Northern dot blot sh owed that all six tumors had a higher level of beta-catenin protein th an surrounding normal tissues, despite containing similar levels of be ta-catenin mRNA, Immunohistochemistry localized beta-catenin throughou t the cell in tumor tissues, although it localized more to the periphe ry in cells from normal tissues, Reverse transcription polymerase chai n reaction showed that the tumors expressed N-cadherin but not E-cadhe rin (a pattern of expression of proteins making up adherens junctions similar to fibrocytes), suggesting that the specific adherens junction s present in epithelial cells are not necessary for beta-catenin funct ion. Increased beta-catenin may cause the growth advantage of cells in this tumor through a nuclear mechanism, The increased protein level, relative to the RNA level, suggests that beta-catenin is degraded at a lower rate compared with normal tissues, In some cases, this is cause d by a somatic mutation resulting in a truncated APC protein.