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Tissue Factor Pathway Inhibitor Gene Polymorphism −33T → C Predicts Improved Disease-Free Survival in Colorectal Cancer

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Tissue factor pathway inhibitor (TFPI) is an anticoagulant with antimetastatic properties. The homozygous CC polymorphism of TFPI (−33T → C) is associated with higher TFPI levels and lower venous thromboembolism risk. This study was the first to evaluate the impact of this polymorphism on disease-free survival (DFS) in cancer patients after curative resection.

Methods

A prospectively maintained tumor bank with 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 for TFPI (−33T → C), factor V Leiden (G1691A), and prothrombin (G20210A) were determined by polymerase chain reaction. Survival analysis was described using the Kaplan–Meier method. Multivariable regression analysis was performed using the Cox proportional hazard model.

Results

Of the 127 patients identified, the CC genotype was found in 11 %. Venous thromboembolism incidence was 18 % in the TT/TC (wild type/heterozygous) genotypes and 7 % in the CC genotype (p = 0.46). The CC genotype was associated with superior DFS (hazard ratio 0.34, 95 % confidence interval 0.14–0.84; p = 0.02) with 5-year DFS of 63 vs. 24 % for CC vs. TT/TC, respectively. In multivariate analysis, CC polymorphism (hazard ratio 0.28, p = 0.008) was independently associated with improved DFS. The prevalence of factor V Leiden (0.8 %) and prothrombin (1.6 %) polymorphisms was too low to detect interaction with TFPI polymorphism or DFS.

Conclusions

These findings indicate that the inherited anticoagulant homozygous −33T → C TFPI polymorphism may protect against colon cancer recurrence and suggests a mediating role for the coagulation system in cancer outcomes.

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Disclosure

The authors declare no conflict of interest.

Funding

This work was supported by a grant from the Cancer Research Society.

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Authors and Affiliations

  1. Division of General Surgery, Department of Surgery, University of Ottawa, Ottawa, ON, Canada

    A. K. Bazzarelli MD, BScPT, A. S. Scheer MD, MSc, R. Seth MD, MSc & R. C. Auer MD, MSc

  2. Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Canada

    L. H. Tai PhD, C. Tanese de Souza DVet & R. C. Auer MD, MSc

  3. Methods Centre, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada

    W. Petrcich MSc

  4. Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Canada

    D. J. Jonker MD, J. A. Maroun MD & M. Carrier MD

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  1. A. K. Bazzarelli MD, BScPT
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  2. A. S. Scheer MD, MSc
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  3. L. H. Tai PhD
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  4. R. Seth MD, MSc
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  5. C. Tanese de Souza DVet
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  8. J. A. Maroun MD
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  10. R. C. Auer MD, MSc
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Correspondence to R. C. Auer MD, MSc.

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Bazzarelli, A.K., Scheer, A.S., Tai, L.H. et al. Tissue Factor Pathway Inhibitor Gene Polymorphism −33T → C Predicts Improved Disease-Free Survival in Colorectal Cancer. Ann Surg Oncol 23, 2274–2280 (2016). https://doi.org/10.1245/s10434-016-5169-4

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  • DOI: https://doi.org/10.1245/s10434-016-5169-4

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