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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

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

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

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

The 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.

Methods

366 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.

Results

Four 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.

Conclusions

A 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.
Appendix
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Metadata
Title
Increased coagulation activity and genetic polymorphisms in the F5, F10 and EPCRgenes are associated with breast cancer: a case-control study
Authors
Mari Tinholt
Marte Kathrine Viken
Anders Erik Dahm
Hans Kristian Moen Vollan
Kristine Kleivi Sahlberg
Øystein Garred
Anne-Lise Børresen-Dale
Anne Flem Jacobsen
Vessela Kristensen
Ida Bukholm
Rolf Kåresen
Ellen Schlichting
Grethe Skretting
Benedicte Alexandra Lie
Per Morten Sandset
Nina Iversen
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-845

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