Increased coagulation activity and genetic polymorphisms in the F5, F10 and EPCR genes are associated with breast cancer: a case-control study.

Mari Tinholt,Ida Bukholm,Grethe Skretting,Anne-Lise Børresen-Dale,Øystein Garred,Ellen Schlichting,Nina Iversen,Marte Kathrine Viken,Kristine Kleivi Sahlberg,Hans Kristian Moen Vollan,Per Morten Sandset,Anders Erik Dahm,Rolf Kåresen,Benedicte Alexandra Lie,Anne Flem Jacobsen,Vessela Kristensen

doi:10.1186/1471-2407-14-845

Abstract

BackgroundThe procoagulant state in cancer increases the thrombotic risk, but also supports tumor progression. To investigate the molecular mechanisms controlling cancer and hemostasis, we conducted a case-control study of genotypic and phenotypic variables of the tissue factor (TF) pathway of coagulation in breast cancer.Methods366 breast cancer patients and 307 controls were genotyped for SNPs (n = 41) in the F2, F3 (TF), F5, F7, F10, TFPI and EPCR genes, and assayed for plasma coagulation markers (thrombin generation, activated protein C (APC) resistance, D-dimer, antithrombin, protein C, protein S, and TF pathway inhibitor (TFPI)). Associations with breast cancer were evaluated using logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs), or the chi-square test.ResultsFour SNPs in F5 (rs12120605, rs6427202, rs9332542 and rs6427199), one in F10 (rs3093261), and one in EPCR (rs2069948) were associated with breast cancer. EPCR rs2069948 was associated with estrogen receptor (ER) and progesterone receptor (PR) positivity, while the SNPs in F5 appeared to follow hormone receptor negative and triple negative patients. The prothrombotic polymorphisms factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) were not associated with breast cancer. High APC resistance was associated with breast cancer in both factor V Leiden non-carriers (OR 6.5, 95% CI 4.1-10.4) and carriers (OR 38.3, 95% CI 6.2-236.6). The thrombin parameters short lag times (OR 5.8, 95% CI 3.7-9.2), short times to peak thrombin (OR 7.1, 95% CI 4.4-11.3), and high thrombin peak (OR 6.1, 95% CI 3.9-9.5) predicted presence of breast cancer, and high D-dimer also associated with breast cancer (OR 2.0, 95% CI 1.3-3.3). Among the coagulation inhibitors, low levels of antithrombin associated with breast cancer (OR 5.7, 95% CI 3.6-9.0). The increased coagulability was not explained by the breast cancer associated SNPs, and was unaffected by ER, PR and triple negative status.ConclusionsA procoagulant phenotype was found in the breast cancer patients. Novel associations with SNPs in F5, F10 and EPCR to breast cancer susceptibility were demonstrated, and the SNPs in F5 were confined to hormone receptor negative and triple negative patients. The study supports the importance of developing new therapeutic strategies targeting coagulation processes in cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-845) contains supplementary material, which is available to authorized users.

Highlights

The procoagulant state in cancer increases the thrombotic risk, and supports tumor progression
It was demonstrated that the endothelial protein C receptor (EPCR) is able to bind the ternary tissue factor (TF)/FVIIa/FXa complex and induce a more efficient protease- activated receptors (PARs)-1 and PAR-2 mediated signaling in endothelial cells [15]
In the present case-control study, we aimed to investigate the role of common single nucleotide polymorphisms (SNPs) in genes involved in the TF pathway of coagulation (i.e., the F2, F3 (TF) F5, F7, F10, EPCR, and Tissue factor pathway inhibitor (TFPI) genes) on the susceptibility of breast cancer

Summary

Introduction

The procoagulant state in cancer increases the thrombotic risk, and supports tumor progression. Plasma levels of the coagulation inhibitors antithrombin and protein C have been shown to decrease, while tissue factor (TF) pathway inhibitor (TFPI) was found to increase during cancer progression [8,9], and several studies have shown that cancer patients acquire activated protein C (APC) resistance [2,3,10,11]. One of the most extensively studied procoagulants involved in cancer is TF Induced by oncogenes, such as K-ras and the epidermal growth factor receptor (EGFR), TF is overexpressed in many cancers. It was demonstrated that the endothelial protein C receptor (EPCR) is able to bind the ternary TF/FVIIa/FXa complex and induce a more efficient PAR-1 and PAR-2 mediated signaling in endothelial cells [15]. EPCR positive breast cancer cells have an increased ability to form tumors in vivo [16]

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