Implications of venous thromboembolism GWAS reported genetic makeup in the clinical outcome of ovarian cancer patients


Ovarian cancer (OC) represents the most lethal gynaecological neoplasia. Conversely, venous thromboembolism (VTE) and OC are intricately connected, with many haemostatic components favouring OC progression. In light of this bilateral relationship, genome-wide association studies (GWAS) have reported several single-nucleotide polymorphisms (SNPs) associated with VTE risk that could be used as predictors of OC clinical outcome for better therapeutic management strategies. Thus, the present study aimed to analyse the impact of VTE GWAS-identified SNPs on the clinical outcome of 336 epithelial ovarian cancer (EOC) patients. Polymorphism genotyping was performed using the TaqMan® Allelic Discrimination methodology. Carriers with the ZFPM2 rs4734879 G allele presented a significantly higher 5-year OS, 10-year OS and disease-free survival (DFS) compared to AA genotype patients with FIGO I/II stages (P = 0.009, P = 0.001 and P = 0.003, respectively). Regarding SLC19A2 rs2038024 polymorphism, carriers with the CC genotype presented a significantly lower 5-year OS, 10-year OS and DFS compared to A allele carriers in the same FIGO subgroup (P < 0.001, P = 0.004 and P = 0.005, respectively). As for CNTN6 rs6764623 polymorphism, carriers with the CC genotype presented a significantly lower 5-year OS compared to A allele carriers with FIGO I/II stages (P = 0.015). As for OTUD7A rs7164569, F11 rs4253417 and PROCR rs10747514, no significant impact on EOC patients’ survival was observed. However, future studies are required to validate these results and uncover the biological mechanisms underlying our results.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Association between ZFPM2 rs4734879 polymorphism and patients’ survival.
Fig. 2: Association between SLC19A2 rs2038024 polymorphism and patients’ survival.
Fig. 3: Association between CNTN6 rs6764623 polymorphism and patients’ 5-year overall survival.


  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Swier N, Versteeg HH. Reciprocal links between venous thromboembolism, coagulation factors and ovarian cancer progression. Thrombosis Res. 2017;150:8–18.

    CAS  Article  Google Scholar 

  3. 3.

    Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014;384:1376–88.

    Article  Google Scholar 

  4. 4.

    Mathieu KB, Bedi DG, Thrower SL, Qayyum A, Bast R Jr. Screening for ovarian cancer: imaging challenges and opportunities for improvement. Ultrasound Obstet Gynecol. 2018;51:293–303.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Papa A, Caruso D, Strudel M, Tomao S, Tomao F. Update on Poly-ADP-ribose polymerase inhibition for ovarian cancer treatment. J Transl Med. 2016;14:267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer J Clinicians. 2016;66:7–30.

    Google Scholar 

  7. 7.

    Pinto R, Assis J, Nogueira A, Pereira C, Coelho S, Brandão M, et al. Pharmacogenomics in epithelial ovarian cancer first-line treatment outcome: validation of GWAS-associated NRG3 rs1649942 and BRE rs7572644 variants in an independent cohort. Pharmacogenomics J. 2019;19:25.

    CAS  Article  Google Scholar 

  8. 8.

    Tavares V, Pinto R, Assis J, Pereira D, Medeiros R. Venous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: linkage to ovarian tumour behaviour. Biochim Biophys Acta 2019:188331.

  9. 9.

    Minors DS. Haemostasis, blood platelets and coagulation. Anaesth Intensive Care Med. 2007;8:214–6.

    Article  Google Scholar 

  10. 10.

    Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk factors for venous thromboembolism. Arterioscler Thromb Vasc Biol. 2012;32:563–8.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Morange PE, Trégouët DA. Current knowledge on the genetics of incident venous thrombosis. J Thromb Haemost. 2013;11:111–21.

    Article  PubMed  Google Scholar 

  12. 12.

    MacArthur J, Bowler E, Cerezo M, Gil L, Hall P, Hastings E, et al. The new NHGRI-EBI catalog of published genome-wide association studies (GWAS catalog). Nucleic Acids Res. 2016;45(D1):D896–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Prat J, Oncology FCoG. FIGO’s staging classification for cancer of the ovary, fallopian tube, and peritoneum: abridged republication. J Gynecol Oncol. 2015;26:87–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Rustin GJS, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21:419–23.

    Article  PubMed  Google Scholar 

  15. 15.

    Huang D, Yi X, Zhang S, Zheng Z, Wang P, Xuan C, et al. GWAS4D: multidimensional analysis of context-specific regulatory variant for human complex diseases and traits. Nucleic Acids Res. 2018;46(W1):W114–W120.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Assis J, Pereira D, Gomes M, Marques D, Marques I, Nogueira A, et al. Influence of CYP3A4 genotypes in the outcome of serous ovarian cancer patients treated with first-line chemotherapy: implication of a CYP3A4 activity profile. Int J Clin Exp Med. 2013;6:552.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Xie X, Rigor P, Baldi P. MotifMap: a human genome-wide map of candidate regulatory motif sites. Bioinformatics. 2009;25:167–74.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Keen JC, Moore HM. The Genotype-Tissue Expression (GTEx) Project: linking clinical data with molecular analysis to advance personalized medicine. J Personalized Med. 2015;5:22–9.

    Article  Google Scholar 

  19. 19.

    Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR. ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res. 2003;31:3568–71.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Saadeh FA, Norris L, O’Toole S, Gleeson N. Venous thromboembolism in ovarian cancer: incidence, risk factors and impact on survival. Eur J Obstet Gynecol Reprod Biol. 2013;170:214–8.

    Article  PubMed  Google Scholar 

  21. 21.

    Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinforma. 2016;54:1.30.31–33.

    Google Scholar 

  22. 22.

    Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, et al. Ensembl 2018. Nucleic Acids Res. 2017;46:D754–61.

    Article  CAS  PubMed Central  Google Scholar 

  23. 23.

    Heineke J, Auger-Messier M, Xu J, Oka T, Sargent MA, York A, et al. Cardiomyocyte GATA4 functions as a stress-responsive regulator of angiogenesis in the murine heart. J Clin Investig. 2007;117:3198–210.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Manuylov N, Smagulova F, Tevosian S. Fog2 excision in mice leads to premature mammary gland involution and reduced Esr1 gene expression. Oncogene. 2007;26:5204.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Hyun S, Lee JH, Jin H, Nam J, Namkoong B, Lee G, et al. Conserved MicroRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K. Cell. 2009;139:1096–108.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558:73.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Nikpay M, Beehler K, Valsesia A, Hager J, Harper M-E, Dent R, et al. Genome-wide identification of circulating-miRNA expression quantitative trait loci reveals the role of several miRNAs in the regulation of cardiometabolic phenotypes. Cardiovasc Res. 2019;115:1629–45.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Crispino JD, Lodish MB, Thurberg BL, Litovsky SH, Collins T, Molkentin JD, et al. Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors. Genes Dev. 2001;15:839–44.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 2017;7:1016.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Amr K, Pawlikowska P, Aoufouchi S, Rosselli F, El‐Kamah G. Whole exome sequencing identifies a new mutation in the SLC19A2 gene leading to thiamine‐responsive megaloblastic anemia in an Egyptian family. Mol Genet Genom Med. 2019;7:e777.

    Google Scholar 

  32. 32.

    Zastre JA, Sweet RL, Hanberry BS, Ye S. Linking vitamin B1 with cancer cell metabolism. Cancer Metab. 2013;1:16.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    LU’O’NG KVQ, Nguyễn LTH. The role of thiamine in cancer: possible genetic and cellular signaling mechanisms. Cancer Genomics-Proteom. 2013;10:169–85.

    Google Scholar 

  34. 34.

    Frank R, Leeper F, Luisi B. Structure, mechanism and catalytic duality of thiamine-dependent enzymes. Cell Mol Life Sci. 2007;64:892.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Krockenberger M, Honig A, Rieger L, Coy J, Sutterlin M, Kapp M, et al. Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. Int J Gynecol Cancer. 2007;17:101–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Schmidt M, Kammerer U, Segerer S, Cramer A, Kohrenhagen N, Dietl J, et al. Glucose metabolism and angiogenesis in granulosa cell tumors of the ovary: activation of Akt, expression of M2PK, TKTL1 and VEGF. Eur J Obstet Gynecol Reprod Biol. 2008;139:72–78.

    CAS  Article  Google Scholar 

  37. 37.

    Xu X, zur Hausen A, Coy JF, Löchelt M. Transketolase‐like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells. Int J Cancer. 2009;124:1330–7.

    CAS  Article  Google Scholar 

  38. 38.

    McLure KG, Takagi M, Kastan MB. NAD+ modulates p53 DNA binding specificity and function. Mol Cell Biol. 2004;24:9958–67.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Yang Z, Ge J, Yin W, Shen H, Liu H, Guo Y. The expression of p53, MDM2 and Ref1 gene in cultured retina neurons of SD rats treated with vitamin B1 and/or elevated pressure. Yan ke xue bao (2016). 2004;20:259–63.

    CAS  Google Scholar 

  40. 40.

    Shin BH, Choi SH, Cho EY, Shin M-J, Hwang K-C, Cho HK, et al. Thiamine attenuates hypoxia-induced cell death in cultured neonatal rat cardiomyocytes. Mol Cells. 2004;18:133–40.

    CAS  PubMed  Google Scholar 

  41. 41.

    Zastre JA, Hanberry BS, Sweet RL, McGinnis AC, Venuti KR, Bartlett MG, et al. Up-regulation of vitamin B1 homeostasis genes in breast cancer. J Nutr Biochem. 2013;24:1616–24.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Gaunt TR, Lowe GD, Lawlor DA, Casas J-P, Day IN. A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array. Eur J Hum Genet. 2013;21:779.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Heit JA, Armasu SM, Asmann YW, Cunningham JM, Matsumoto ME, Petterson TM, et al. A genome‐wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24. 2 and 9q. J Thromb Haemost. 2012;10:1521–31.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP. Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol: Mechanisms Dis. 2012;7:423–67.

    CAS  Article  Google Scholar 

  46. 46.

    Nakajima EC, Van, Houten B. Metabolic symbiosis in cancer: refocusing the Warburg lens. Mol Carcinog. 2013;52:329–37.

    CAS  Article  Google Scholar 

  47. 47.

    Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17:1498.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    He H, Li W, Liyanarachchi S, Srinivas M, Wang Y, Akagi K, et al. Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer. Proc Natl Acad Sci. 2015;112:6128–33.

    CAS  Article  Google Scholar 

  49. 49.

    Quillard T, Charreau B. Impact of notch signaling on inflammatory responses in cardiovascular disorders. Int J Mol Sci. 2013;14:6863–88.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Mu D, Xu Y, Zhao T, Watanabe K, Xiao ZC, Ye H. Cntn6 deficiency impairs allocentric navigation in mice. Brain Behav. 2018;8:e00969.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Cui X-Y, Hu Q-D, Tekaya M, Shimoda Y, Ang B-T, Nie D-Y, et al. NB-3/Notch1 pathway via Deltex1 promotes neural progenitor cell differentiation into oligodendrocytes. J Biol Chem. 2004;279:25858–65.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Wong C-M, Wang Y, Lee JTH, Huang Z, Wu D, Xu A, et al. Adropin is a brain membrane-bound protein regulating physical activity via the NB-3/Notch signaling pathway in mice. J Biol Chem. 2014;289:25976–86.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Rose SL, Kunnimalaiyaan M, Drenzek J, Seiler N. Notch 1 signaling is active in ovarian cancer. Gynecol Oncol. 2010;117:130–3.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    McAuliffe SM, Morgan SL, Wyant GA, Tran LT, Muto KW, Chen YS, et al. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc Natl Acad Sci. 2012;109:E2939–48.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Espinoza I, Miele L. Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett. 2013;341:41–45.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Gupta N, Xu Z, El-Sehemy A, Steed H, Fu Y. Notch3 induces epithelial–mesenchymal transition and attenuates carboplatin-induced apoptosis in ovarian cancer cells. Gynecologic Oncol. 2013;130:200–6.

    CAS  Article  Google Scholar 

  57. 57.

    Ahmed N, Abubaker K, Findlay J, Quinn M. Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Curr Cancer Drug Targets. 2010;10:268–78.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Groeneweg JW, Foster R, Growdon WB, Verheijen RH, Rueda BR. Notch signaling in serous ovarian cancer. J Ovarian Res. 2014;7:95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Chiaramonte R, Colombo M, Bulfamante G, Falleni M, Tosi D, Garavelli S, et al. Notch pathway promotes ovarian cancer growth and migration via CXCR4/SDF1α chemokine system. Int J Biochem Cell Biol. 2015;66:134–40.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Ranganathan P, Weaver KL, Capobianco AJ. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 2011;11:338.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Xu Z, Pei L, Wang L, Zhang F, Hu X, Gui Y. Snail1-dependent transcriptional repression of Cezanne2 in hepatocellular carcinoma. Oncogene. 2014;33:2836.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Coordinators NR. Database resources of the national center for biotechnology information. Nucleic Acids Res. 2018;46:D8.

    Article  CAS  Google Scholar 

  63. 63.

    Enesa K, Zakkar M, Chaudhury H, Luong LA, Rawlinson L, Mason JC, et al. NF-κB suppression by the deubiquitinating enzyme cezanne a novel negative feedback loop in pro-inflammatory signaling. J Biol Chem. 2008;283:7036–45.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med. 2000;342:696–701.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Seligsohn U. Factor XI in haemostasis and thrombosis: past, present and future. Thromb Haemost. 2007;98:84–89.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Versteeg HH, Spek CA, Richel DJ, Peppelenbosch MP. Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene. 2004;23:410.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Von dem Borne P, Meijers J, Bouma B. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood. 1995;86:3035–42.

    Article  Google Scholar 

  68. 68.

    Emsley J, McEwan PA, Gailani D. Structure and function of factor XI. Blood. 2010;115:2569–77.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Ahmad R, Knafo L, Xu J, Sindhu ST, Menezes J, Ahmad A. Thrombin induces apoptosis in human tumor cells. Int J Cancer. 2000;87:707–15.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Schiller H, Bartscht T, Arlt A, Zahn M, Seifert A, Bruhn T, et al. Thrombin as a survival factor for cancer cells: thrombin activation in malignant effusions in vivo and inhibition of idarubicin-induced cell death in vitro. Int J Clin Pharmacol Therapeutics. 2002;40:329–35.

    CAS  Article  Google Scholar 

  71. 71.

    Brass LF. Thrombin and platelet activation. Chest. 2003;124:18S–25S.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Tesfamariam B. Involvement of platelets in tumor cell metastasis. Pharmacol Therapeutics. 2016;157:112–9.

    CAS  Article  Google Scholar 

  73. 73.

    Nierodzik ML, Karpatkin S. Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell. 2006;10:355–62.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Van Hinsbergh VW, Collen A, Koolwijk P. Role of fibrin matrix in angiogenesis. Ann N Y Acad Sci. 2001;936:426–37.

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood. 2004;104:2746–51.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Handin N. Identification of new regulatory mechanisms that determine coagulation FXI plasma concentration. 2015.

  77. 77.

    Novel mechanisms regulating Factor XI plasma levels. Journal of Thrombosis and Haemostasis. WILEY-BLACKWELL 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: 2016.

  78. 78.

    Saposnik B, Reny J-L, Gaussem P, Emmerich J, Aiach M, Gandrille S. A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood. 2004;103:1311–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Tsuneyoshi N, Fukudome K, Horiguchi S-i, Ye X, Matsuzaki M, Toi M, et al. Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines. Thromb Haemost. 2001;85:356–61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Beaulieu LM, Church FC. Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Exp Cell Res. 2007;313:677–87.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Yan Q, Xiaorong Z, Zhang Z, Bing W, Feng Y, Hong B. Prevalence of protein C receptor (PROCR) is associated with inferior clinical outcome in Breast invasive ductal carcinoma. Pathol-Res Pract. 2017;213:1173–9.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Wang Q, Tang Y, Wang T, Yang HL, Wang X, Ma H, et al. EPCR promotes MGC803 human gastric cancer cell tumor angiogenesis in vitro through activating ERK1/2 and AKT in a PAR1‑dependent manner. Oncol Lett. 2018;16:1565–70.

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Wojtukiewicz M, Hempel D, Sierko E, Tucker S, Honn K. Endothelial protein C receptor (EPCR), protease activated receptor-1 (PAR-1) and their interplay in cancer growth and metastatic dissemination. Cancers. 2019;11:51.

    CAS  Article  PubMed Central  Google Scholar 

  84. 84.

    Skirnisdottir I, Seidal T, Åkerud H. The relationship of the angiogenesis regulators VEGF-A, VEGF-R1 and VEGF-R2 to p53 status and prognostic factors in epithelial ovarian carcinoma in FIGO-stages I-II. Int J Oncol. 2016;48:998–1006.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Cotsapas C, Hafler DA. Immune-mediated disease genetics: the shared basis of pathogenesis. Trends Immunol. 2013;34:22–26.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Amirkhosravi A, Bigsby G IV, Desai H, Rivera-Amaya M, Coll E, Robles-Carrillo L, et al. Blood clotting activation analysis for preoperative differentiation of benign versus malignant ovarian masses. Blood Coagul Fibrinolysis. 2013;24:510–7.

    Article  PubMed  Google Scholar 

  87. 87.

    Kim J-y, Al-Hilal TA, Chung SW, Kim SY, Ryu GH, Son WC, et al. Antiangiogenic and anticancer effect of an orally active low molecular weight heparin conjugates and its application to lung cancer chemoprevention. J Controlled Release. 2015;199:122–31.

    CAS  Article  Google Scholar 

Download references


We would like to thank the Liga Portuguesa Contra o Cancro-Centro Regional do Norte (LPCC-NRN2020-VT), Ministério da Saúde de Portugal (CFICS-45/2007), IPO-Porto Projects (CI-IPOP-22-2015 and CI-IPOP-91-2018) and Fundação para a Ciência e Tecnologia (FCT).

Author information



Corresponding author

Correspondence to Rui Medeiros.

Ethics declarations

Conflict of interest

The authors have no relevant affiliations with any organisation with a financial interest in or conflict with the subject matter discussed in this manuscript apart from those disclosed. Therefore, the authors declare no conflict of interest. No writing assistance was required during the production of this manuscript.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tavares, V., Pinto, R., Assis, J. et al. Implications of venous thromboembolism GWAS reported genetic makeup in the clinical outcome of ovarian cancer patients. Pharmacogenomics J (2020).

Download citation


Quick links