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

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...

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Bibliographic Details
Published in:BMC cancer 2014-11, Vol.14 (1), p.845-845
Main Authors: Tinholt, Mari, Viken, Marte Kathrine, Dahm, Anders Erik, Vollan, Hans Kristian Moen, Sahlberg, Kristine Kleivi, Garred, Oystein, Børresen-Dale, Anne-Lise, Jacobsen, Anne Flem, Kristensen, Vessela, Bukholm, Ida, Kåresen, Rolf, Schlichting, Ellen, Skretting, Grethe, Lie, Benedicte Alexandra, Sandset, Per Morten, Iversen, Nina
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Alleles
Antigens, CD - genetics
Blood Coagulation - genetics
Breast cancer
Breast Neoplasms - blood
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Case-Control Studies
Endothelial Protein C Receptor
Factor V - genetics
Factor X - genetics
Female
Genes
Genetic Association Studies
Genetic Predisposition to Disease
Haplotypes
Hemostasis
Humans
Linkage Disequilibrium
Medical research
Middle Aged
Neoplasm Staging
Odds Ratio
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Receptors, Cell Surface - genetics
Risk
Signal Transduction
Studies
Thromboplastin - metabolism
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Summary: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. 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. 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. 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.
ISSN:1471-2407
1471-2407
DOI:10.1186/1471-2407-14-845