Association of tissue factor pathway inhibitor gene polymorphism -33T→C with disease-free survival in colorectal cancer.

Abstract

395 Background: Tissue Factor Pathway Inhibitor (TFPI) is an anticoagulant protein exhibiting antimetastatic properties in preclinical models. The homozygous CC polymorphism on intron 7 of TFPI (-33T-->C) is associated with higher TFPI protein levels and a lower risk of venous thromboembolism (VTE). The present study is the first to evaluate the impact of the inherited TFPI polymorphism on disease-free survival (DFS) in cancer patients following curative resection. Methods: A prospectively maintained colorectal tumour bank with associated clinical data was used to identify patients who underwent curative surgery for colorectal cancer between 1994 and 2006. Germline DNA was extracted from formalin fixed, paraffin embedded normal colonic mucosa. Single nucleotide polymorphisms (SNPs) for Tissue Factor Pathway Inhibitor (TFPI, -33T-->C), Factor V Leiden (FVL, G1691A), and Prothrombin (PT, G20210A) were determined by polymerase chain reaction. DFS was described using the Kaplan-Meier method. Multivariable regression analysis, with known prognostic factors, was performed using the Cox Proportional Hazard model. Results: Of the 139 patients identified, the prevalence of the wildtype (TT) TFPI genotype was found in 57.3% of samples, the heterozygous genotype (TC) in 29.4%, and the homozygous genotype (CC) in 10.5%. The incidence of VTE was 21.6% in the TT/TC genotypes and 6.7% in the CC genotype (p=0.4). The CC genotype was associated with superior DFS (HR 0.38, [95%CI 0.17-0.88]; p=.02) with 5 year DFS 56.3% vs. 24.6% for CC vs. TT/TC respectively. In multivariate analysis female sex (HR=0.61, p=.02), chemotherapy (HR=0.66, p=.05), node negative (HR=0.47, p=.005) and TFPI CC polymorphism (HR=0.35, p=.01) were independently associated with improved DFS. The prevalence of FVL (0.7%) and PT (2.2%) polymorphisms was too low to detect any interaction with TFPI polymorphism and DFS. Conclusions: These findings indicate that the inherited anticoagulant homozygous -33T-->C TFPI polymorphism may protect against colon cancer recurrence, and suggest a causal role for the coagulation system in cancer outcomes.