An association between the 4G polymorphism in the PAI-1 promoter and the development of aggressive fibromatosis (desmoid tumor) in familial adenomatous polyposis patients

Abstract

Aggressive fibromatosis is a mesenchymal neoplasm associated with mutations resulting in beta-catenin mediated transcriptional activation. Plasminogen activator inhibitor-1 (PAI-1) is expressed at a high level in aggressive fibromatosis, and using transgenic mice, we found that PAI-1 plays an important role in aggressive fibromatosis tumor formation. Familial adenomatous polyposis is associated with Adenomatous Polyposis Coli gene mutations resulting in beta-catenin mediated transcriptional activation, yet only some patients develop aggressive fibromatosis. Since PAI-1 expression is influenced by a promoter 4G/5G polymorphism, we investigated the incidence of this polymorphism in familial adenomatous polyposis patients who did and who did not develop aggressive fibromatosis, as well as sporadic aggressive fibromatosis patients. There was a trend towards association of the 4G allele (associated with high PAI-1 expression) with the development of aggressive fibromatosis in familial adenomatous polyposis patients (50% vs. 19%, P = 0.1). In familial adenomatous polyposis patients who did not develop aggressive fibromatosis, there was a significantly lower proportion of patients with a 4G allele compared to the healthy control (19% vs. 51%, P = 0.0286). The lower incidence of 4G polymorphism in the PAI-1 promoter may be preventive against the development of aggressive fibromatosis. This data provides additional evidence supporting an important role for PAI-1 in the pathogenesis of aggressive fibromatosis.

Genetic polymorphism of the plasminogen activator inhibitor‐1 is associated with an increased risk of endometrial cancer

“…Our results revealed PAI‐I 4G/4G genotype significantly increase the risk of endometrial carcinoma and the elevated risk reached statistic significance in the whole study group and the subgroups of those patients over 50 years old, endometrioid type and low stage (stages I–II) endometrial cancer. The finding are in accordance with those of previous studies that showed PAI‐1‐675 4G/4G genotype is associated with increased risk for oral cancer 11, 13, aggressive fibromatosis 14, and breast cancer 15.…”

Desmoid cell motility is induced in vitro by rhEGF

“…4,5 Less frequently reported aberrations include reduced expression of the Retinoblastoma (RB) tumor suppressor gene, 6 upregulation of Wilms' tumor gene 1 (WT1), 7 and polymorphism in the plasminogen activator inhibitor 1 (PAI-1) promoter. 8 Epidermal growth factor (EGF) and transforming growth factor alpha (TGFa) are essential participants in the process of wound healing and their common receptor (EGFR) is typically upregulated in uteroplacental tissues during childbirth. [9][10][11][12][13] Overexpression of EGFR also correlates with tumor aggressiveness in a variety of cancer types.…”