title: Increased coagulation activity and genetic polymorphisms in the F5, F10 and EPCR genes are associated with breast cancer: a case-control study.
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.
authors.forename: Mari
authors.initials: M
authors.lastname: Tinholt
authors.forename: Marte Kathrine
authors.initials: MK
authors.lastname: Viken
authors.forename: Anders Erik
authors.initials: AE
authors.lastname: Dahm
authors.forename: Hans Kristian Moen
authors.initials: HK
authors.lastname: Vollan
authors.forename: Kristine Kleivi
authors.initials: KK
authors.lastname: Sahlberg
authors.forename: Oystein
authors.initials: O
authors.lastname: Garred
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Anne Flem
authors.initials: AF
authors.lastname: Jacobsen
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.forename: Ida
authors.initials: I
authors.lastname: Bukholm
authors.forename: Rolf
authors.initials: R
authors.lastname: Kåresen
authors.forename: Ellen
authors.initials: E
authors.lastname: Schlichting
authors.forename: Grethe
authors.initials: G
authors.lastname: Skretting
authors.forename: Benedicte Alexandra
authors.initials: BA
authors.lastname: Lie
authors.forename: Per Morten
authors.initials: PM
authors.lastname: Sandset
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. nina.iversen@medisin.uio.no.
authors.forename: Nina
authors.initials: N
authors.lastname: Iversen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015703:Antigens, CD / Q000235:genetics*; D001777:Blood Coagulation / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D000074283:Endothelial Protein C Receptor; D005165:Factor V / Q000235:genetics*; D005170:Factor X / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006487:Hemostasis; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D012306:Risk; D015398:Signal Transduction; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011956:Receptors, Cell Surface; D005165:Factor V; D005170:Factor X; D013925:Thromboplastin