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.
Subscribe to Journal
Get full journal access for 1 year
only $83.17 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Swier N, Versteeg HH. Reciprocal links between venous thromboembolism, coagulation factors and ovarian cancer progression. Thrombosis Res. 2017;150:8–18.
Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014;384:1376–88.
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.
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.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer J Clinicians. 2016;66:7–30.
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.
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.
Minors DS. Haemostasis, blood platelets and coagulation. Anaesth Intensive Care Med. 2007;8:214–6.
Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk factors for venous thromboembolism. Arterioscler Thromb Vasc Biol. 2012;32:563–8.
Morange PE, Trégouët DA. Current knowledge on the genetics of incident venous thrombosis. J Thromb Haemost. 2013;11:111–21.
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.
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.
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.
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.
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.
Xie X, Rigor P, Baldi P. MotifMap: a human genome-wide map of candidate regulatory motif sites. Bioinformatics. 2009;25:167–74.
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.
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.
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.
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.
Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, et al. Ensembl 2018. Nucleic Acids Res. 2017;46:D754–61.
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.
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.
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.
Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51.
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.
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.
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.
Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 2017;7:1016.
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.
Zastre JA, Sweet RL, Hanberry BS, Ye S. Linking vitamin B1 with cancer cell metabolism. Cancer Metab. 2013;1:16.
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.
Frank R, Leeper F, Luisi B. Structure, mechanism and catalytic duality of thiamine-dependent enzymes. Cell Mol Life Sci. 2007;64:892.
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.
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.
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.
McLure KG, Takagi M, Kastan MB. NAD+ modulates p53 DNA binding specificity and function. Mol Cell Biol. 2004;24:9958–67.
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.
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.
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.
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.
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.
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.
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.
Nakajima EC, Van, Houten B. Metabolic symbiosis in cancer: refocusing the Warburg lens. Mol Carcinog. 2013;52:329–37.
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.
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.
Quillard T, Charreau B. Impact of notch signaling on inflammatory responses in cardiovascular disorders. Int J Mol Sci. 2013;14:6863–88.
Mu D, Xu Y, Zhao T, Watanabe K, Xiao ZC, Ye H. Cntn6 deficiency impairs allocentric navigation in mice. Brain Behav. 2018;8:e00969.
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.
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.
Rose SL, Kunnimalaiyaan M, Drenzek J, Seiler N. Notch 1 signaling is active in ovarian cancer. Gynecol Oncol. 2010;117:130–3.
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.
Espinoza I, Miele L. Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett. 2013;341:41–45.
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.
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.
Groeneweg JW, Foster R, Growdon WB, Verheijen RH, Rueda BR. Notch signaling in serous ovarian cancer. J Ovarian Res. 2014;7:95.
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.
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.
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.
Coordinators NR. Database resources of the national center for biotechnology information. Nucleic Acids Res. 2018;46:D8.
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.
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.
Seligsohn U. Factor XI in haemostasis and thrombosis: past, present and future. Thromb Haemost. 2007;98:84–89.
Versteeg HH, Spek CA, Richel DJ, Peppelenbosch MP. Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene. 2004;23:410.
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.
Emsley J, McEwan PA, Gailani D. Structure and function of factor XI. Blood. 2010;115:2569–77.
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.
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.
Brass LF. Thrombin and platelet activation. Chest. 2003;124:18S–25S.
Tesfamariam B. Involvement of platelets in tumor cell metastasis. Pharmacol Therapeutics. 2016;157:112–9.
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.
Van Hinsbergh VW, Collen A, Koolwijk P. Role of fibrin matrix in angiogenesis. Ann N Y Acad Sci. 2001;936:426–37.
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.
Handin N. Identification of new regulatory mechanisms that determine coagulation FXI plasma concentration. 2015.
Novel mechanisms regulating Factor XI plasma levels. Journal of Thrombosis and Haemostasis. WILEY-BLACKWELL 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: 2016.
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.
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.
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.
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.
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.
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.
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.
Cotsapas C, Hafler DA. Immune-mediated disease genetics: the shared basis of pathogenesis. Trends Immunol. 2013;34:22–26.
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.
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.
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).
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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). https://doi.org/10.1038/s41397-020-00201-9