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Journal of Thrombosis and Thrombolysis

20-04-2024 | Cervical Cancer

Haemostatic gene variations in cervical cancer-associated venous thrombosis: considerations for clinical strategies

Authors: Beatriz Vieira Neto, Valéria Tavares, José Brito da Silva, Joana Liz-Pimenta, Inês Soares Marques, Lurdes Salgado, Luísa Carvalho, Deolinda Pereira, Rui Medeiros

Published in: Journal of Thrombosis and Thrombolysis

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Abstract

Venous thromboembolism (VTE) is a life-threatening haemostatic disease frequently diagnosed among the cancer population. The Khorana Score is currently the primal risk assessment model to stratify oncological patients according to their susceptibility to VTE, however, it displays a limited performance. Meanwhile, intensive research on VTE pathophysiology in the general population has uncovered a range of single-nucleotide polymorphisms (SNPs) associated with the condition. Nonetheless, their predictive ability concerning cancer-associated thrombosis (CAT) is controversial. Cervical cancer (CC) patients undergoing chemoradiotherapy often experience VTE, which negatively affects their survival. Thus, aiming for an improvement in thromboprophylaxis, new thrombotic biomarkers, including SNPs, are currently under investigation. In this study, the predictive capability of haemostatic gene SNPs on CC-related VTE and their prognostic value regardless of VTE were explored. Six SNPs in haemostatic genes were evaluated. A total of 401 CC patients undergoing chemoradiotherapy were enrolled in a retrospective cohort study. The implications for the time to VTE occurrence and overall survival (OS) were assessed. CAT considerably impacted the CC patients’ OS (log-rank test, P < 0.001). SERPINE1 rs2070682 (T > C) showed a significant association with the risk of CC-related VTE (CC/CT vs. TT, log-rank test, P = 0.002; C allele, Cox model, hazard ratio (HR) = 6.99 and P = 0.009), while F2 rs1799963 (G > A) demonstrated an important prognostic value regardless of VTE (AA/AG vs. GG, log-rank test, P = 0.020; A allele, Cox model, HR = 2.76 and P = 0.026). For the remaining SNPs, no significant associations were detected. The polymorphisms SERPINE1 rs2070682 and F2 rs1799963 could be valuable tools in clinical decision-making, aiding in thromboprophylaxis and CC management, respectively.

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Literature
1.
Mensah GA, Roth GA, Fuster V (2019) The global burden of cardiovascular diseases and risk factors: 2020 and beyond. American College of Cardiology Foundation Washington, DC, pp 2529–2532
2.
Tavares V, Pinto R, Assis J, Coelho S, Brandao M, Alves S, Pereira D, Medeiros R (2021) Implications of venous thromboembolism GWAS reported genetic makeup in the clinical outcome of ovarian cancer patients. Pharmacogenomics J 21(2):222–232PubMedCrossRef
3.
DeVita VT, Lawrence TS, Rosenberg SA (2008) DeVita, Hellman, and Rosenberg’s cancer: principles & practice of oncology. Lippincott Williams & Wilkins
4.
de Araujo Trugilho I, Renni MJP, Medeiros GC, Thuler LCS, Bergmann A (2020) Incidence and factors associated with venous thromboembolism in women with gynecologic cancer. Thromb Res 185:49–54CrossRef
5.
6.
Lim W, Le Gal G, Bates SM, Righini M, Haramati LB, Lang E, Kline JA, Chasteen S, Snyder M, Patel P (2018) American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism. Blood Adv 2(22):3226–3256PubMedPubMedCentralCrossRef
7.
Liz-Pimenta J, Tavares V, Neto BV, Santos JM, Guedes CB, Araújo A, Khorana AA, Medeiros R (2023) Thrombosis and cachexia in cancer: two partners in crime? Crit Rev Oncol/Hematol 103989
8.
Cushman M (2005) Inherited risk factors for venous thrombosis. ASH Educ Program Book 2005(1):452–457
9.
Navarrete S, Solar C, Tapia R, Pereira J, Fuentes E, Palomo I (2023) Pathophysiology of deep vein thrombosis. Clin Experimental Med 23(3):645–654CrossRef
10.
Kaur S, Ali A, Ahmad U, Siahbalaei Y, Pandey A, Singh B (2019) Role of single nucleotide polymorphisms (SNPs) in common migraine. Egypt J Neurol Psychiatry Neurosurg 55(1):1–7CrossRef
11.
Tavares V, Pinto R, Assis J, Pereira D, Medeiros R (2020) Venous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: linkage to ovarian tumour behaviour. Biochim et Biophys Acta (BBA)-Reviews Cancer 1873(1):188331CrossRef
12.
Fernandes CJ, Morinaga LTK, Alves JLJ, Castro MA, Calderaro D, Jardim CVP, Souza R (2019) Cancer-associated thrombosis: the when, how and why. Eur Respir Rev 28(151)
13.
Lutsey PL, Zakai NA (2023) Epidemiology and prevention of venous thromboembolism. Nat Reviews Cardiol 20(4):248–262CrossRef
14.
Satoh T, Matsumoto K, Tanaka YO, Akiyama A, Nakao S, Sakurai M, Ochi H, Onuki M, Minaguchi T, Sakurai H (2013) Incidence of venous thromboembolism before treatment in cervical cancer and the impact of management on venous thromboembolism after commencement of treatment. Thromb Res 131(4):e127–e132PubMedCrossRef
15.
Tavares V, Neto BV, Vilas-Boas MI, Pereira D, Medeiros R (2022) Impact of hereditary thrombophilia on cancer-associated thrombosis, tumour susceptibility and progression: a review of existing evidence, Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 188778
16.
Tavares V, Neto BV, Marques IS, Assis J, Pereira D, Medeiros R (2023) Cancer-associated thrombosis: what about microRNAs targeting the tissue factor coagulation pathway? Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 189053
17.
Khorana AA, Mackman N, Falanga A, Pabinger I, Noble S, Ageno W, Moik F, Lee AY (2022) Cancer-associated venous thromboembolism. Nat Reviews Disease Primers 8(1):1–18
18.
Neto BV, Tavares V, da Silva JB, Liz-Pimenta J, Marques IS, Carvalho L, Salgado L, Pereira D, Medeiros R (2023) Thrombogenesis-associated genetic determinants as predictors of thromboembolism and prognosis in cervical cancer. Sci Rep 13(1):9519PubMedPubMedCentralCrossRef
19.
Prat J, Oncology FCoG (2015) FIGO’s staging classification for cancer of the ovary, fallopian tube, and peritoneum: abridged republication. J Gynecol Oncol 26(2):87–89PubMedPubMedCentralCrossRef
20.
Quinn BA, Deng X, Colton A, Bandyopadhyay D, Carter JS, Fields EC (2019) Increasing age predicts poor cervical cancer prognosis with subsequent effect on treatment and overall survival. Brachytherapy 18(1):29–37PubMedCrossRef
21.
Wright JD, Matsuo K, Huang Y, Tergas AI, Hou JY, Khoury-Collado F, Clair CMS, Ananth CV, Neugut AI, Hershman DL (2019) Prognostic performance of the 2018 International Federation of Gynecology and Obstetrics cervical cancer staging guidelines. Obstet Gynecol 134(1):49PubMedPubMedCentralCrossRef
22.
Khorana AA, Mackman N, Falanga A, Pabinger I, Noble S, Ageno W, Moik F, Lee AY (2022) Cancer-associated venous thromboembolism. Nat Reviews Disease Primers 8(1):11PubMedCrossRef
23.
Falanga A, Marchetti M (2023) Cancer-associated thrombosis: enhanced awareness and pathophysiologic complexity. J Thromb Haemost
24.
Sang Y, Roest M, de Laat B, de Groot PG, Huskens D (2021) Interplay between platelets and coagulation. Blood Rev 46:100733PubMedCrossRef
25.
26.
Jacobson G, Lammli J, Zamba G, Hua L, Goodheart MJ (2009) Thromboembolic events in patients with cervical carcinoma: incidence and effect on survival. Gynecol Oncol 113(2):240–244PubMedCrossRef
27.
Matsuo K, Moeini A, Machida H, Fullerton ME, Shabalova A, Brunette LL, Roman LD (2016) Significance of venous thromboembolism in women with cervical cancer. Gynecol Oncol 142(3):405–412PubMedPubMedCentralCrossRef
28.
Wun T, Law L, Harvey D, Sieracki B, Scudder SA, Ryu JK (2003) Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. CA Cancer J Clin 98(7):1514–1520
29.
Temkin S, Hellmann M, Serur E, Lee Y-C, Abulafia O (2006) Erythropoietin administration during primary treatment for locally advanced cervical carcinoma is associated with poor response to radiation. Int J Gynecol Cancer 16(5)
30.
Pötter R, Dimopoulos J, Bachtiary B, Sissolak G, Klos B, Rheinthaller A, Kirisits C (2006) Knocke-Abulesz, 3D conformal HDR-brachy-and external beam therapy plus simultaneous cisplatin for high-risk cervical cancer: clinical experience with 3 year follow-up. Radiother Oncol 79(1):80–86PubMedCrossRef
31.
Thomas G, Ali S, Hoebers FJ, Darcy KM, Rodgers WH, Patel M, Abulafia O, Lucci JA III, Begg AC (2008) Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 108(2):317–325PubMedCrossRef
32.
Jacobson GM, Kamath RS, Smith BJ, Goodheart MJ (2005) Thromboembolic events in patients treated with definitive chemotherapy and radiation therapy for invasive cervical cancer. Gynecol Oncol 96(2):470–474PubMedCrossRef
33.
Mulder FI, Horvàth-Puhó E, van Es N, Van Laarhoven H, Pedersen L, Moik F, Ay C, Büller H, Sørensen H (2021) Venous thromboembolism in cancer patients: a population-based cohort study, blood. J Am Soc Hematol 137(14):1959–1969
34.
Howe K.L., Achuthan P., Allen J., Allen J., Alvarez-Jarreta J., Amode M.R., Armean I.M., Azov A.G., Bennett R., Bhai J. (2021) Ensembl 2021. Nucleic Acids Res 49D1:D884–D891
35.
Ju H, Lim B, Kim M, Noh SM, Kim WH, Ihm C, Choi BY, Kim YS, Kang C (2010) SERPINE1 intron polymorphisms affecting gene expression are associated with diffuse-type gastric cancer susceptibility. Cancer 116(18):4248–4255PubMedCrossRef
36.
Siokas V, Dardiotis E, Sokolakis T, Kotoula M, Tachmitzi SV, Chatzoulis DZ, Almpanidou P, Stefanidis I, Hadjigeorgiou GM, Tsironi EE (2017) Plasminogen activator inhibitor type-1 tag single-nucleotide polymorphisms in patients with diabetes mellitus type 2 and diabetic retinopathy. Curr Eye Res 42(7):1048–1053PubMedCrossRef
37.
Williams PT (2021) Quantile-specific heritability of plasminogen activator inhibitor type‐1 (PAI‐1, aka SERPINE1) and other hemostatic factors. J Thromb Haemost 19(10):2559–2571PubMedCrossRef
38.
Zhang P, Chaldebas M, Ogishi M, Al Qureshah F, Ponsin K, Feng Y, Rinchai D, Milisavljevic B, Han JE, Moncada-Vélez M (2023) Genome-wide detection of human intronic AG-gain variants located between splicing branchpoints and canonical splice acceptor sites. Proc Natl Acad Sci 120(46):e2314225120PubMedPubMedCentralCrossRef
39.
Johnson DC, Corthals S, Ramos C, Hoering A, Cocks K, Dickens NJ, Haessler J, Goldschmidt H, Child JA, Bell SE (2008) Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping, blood. J Am Soc Hematol 112(13):4924–4934
40.
Furuya H, Sasaki Y, Chen R, Peres R, Hokutan K, Murakami K, Kim N, Chan OT, Pagano I, Dyrskjøt L (2022) PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity. Sci Rep 12(1):12186PubMedPubMedCentralCrossRef
41.
42.
43.
Ünlü B, Versteeg HH (2014) Effects of tumor-expressed coagulation factors on cancer progression and venous thrombosis: is there a key factor? Thromb Res 133:S76–S84PubMedCrossRef
44.
Steri M, Idda ML, Whalen MB, Orrù V (2018) Genetic variants in mRNA untranslated regions. Wiley Interdisciplinary Reviews: RNA 9(4):e1474PubMedCrossRef
45.
Demirci FYK, Dressen AS, Kammerer CM, Barmada MM, Kao AH, Ramsey-Goldman R, Manzi S, Kamboh MI (2011) Functional polymorphisms of the coagulation factor II gene (F2) and susceptibility to systemic lupus erythematosus. J Rhuematol 38(4):652–657CrossRef
46.
Trégouët DA, Morange PE (2018) What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies. Br J Haematol 180(3):335–345PubMedCrossRef
47.
Xia X, Fu J, Wu T, Chen W, Jiang S, Lv M, Zhang J (2022) Effect of gene polymorphism on bleeding complications in Chinese Han patients taking warfarin. Eur J Clin Pharmacol 1–10
48.
Vossen CY, Hoffmeister M, Chang-Claude JC, Rosendaal FR, Brenner H (2011) Clotting factor gene polymorphisms and colorectal cancer risk. J Clin Oncol 29(13):1722–1727PubMedCrossRef
49.
Baghad I, Erguibi D, Chehab F, Nadifi S (2017) Risk of colorectal cancer and clotting factor gene polymorphisms in Moroccan Population. Int J Adv Res 5(8):1141CrossRef
50.
51.
Barco S, Klok FA, Mahé I, Marchena PJ, Ballaz A, Rubio CM, Adarraga MD, Mastroiacovo D, Konstantinides SV, Monreal M (2019) Impact of sex, age, and risk factors for venous thromboembolism on the initial presentation of first isolated symptomatic acute deep vein thrombosis. Thromb Res 173:166–171PubMedCrossRef
52.
Montagnana M, Favaloro EJ, Franchini M, Guidi GC, Lippi G (2010) The role of ethnicity, age and gender in venous thromboembolism. J Thromb Thrombolysis 29:489–496PubMedCrossRef
53.
Scarabin P-Y, Vissac A-M, Kirzin J-M, Bourgeat P, Amiral J, Agher R, Guize L (1996) Population correlates of coagulation factor VII: importance of age, sex, and menopausal status as determinants of activated factor VII, Arterioscler. Thromb Vasc Biol 16(9):1170–1176CrossRef
54.
Attard C, Van der Straaten T, Karlaftis V, Monagle P, Ignjatovic V (2013) Developmental hemostasis: age-specific differences in the levels of hemostatic proteins. J Thromb Haemost 11(10):1850–1854PubMedCrossRef
55.
Mari D, Ogliari G, Castaldi D, Vitale G, Bollini EM, Lio D (2008) Hemostasis and ageing, Immunity & Ageing 5(1) 1–4
56.
Favaloro EJ, Franchini M, Lippi G (2014) Aging hemostasis: changes to laboratory markers of hemostasis as we age—a narrative review, seminars in thrombosis and hemostasis. Thieme Medical, pp 621–633
57.
Pieters M, Wolberg AS (2019) Fibrinogen and fibrin: An illustrated review, Research and practice in thrombosis and haemostasis 3(2) 161–172
58.
Luyendyk JP, Schoenecker JG, Flick MJ (2019) The multifaceted role of fibrinogen in tissue injury and inflammation, blood. J Am Soc Hematol 133(6):511–520
59.
Jarvis KB, LeBlanc M, Tulstrup M, Nielsen RL, Albertsen BK, Gupta R, Huttunen P, Jónsson ÓG, Rank CU, Ranta S (2019) Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia–A NOPHO ALL2008 study. Thromb Res 184:92–98PubMedCrossRef
60.
Peschek LS, Hobusch GM, Funovics PT, Willegger M, Schmid MP, Amann G, Lamm W, Brodowicz T, Ay C, Windhager R (2023) High fibrinogen levels are associated with poor survival in patients with liposarcoma. Sci Rep 13(1):8608PubMedPubMedCentralCrossRef
61.
Paulsen B, Skille H, Smith EN, Hveem K, Gabrielsen ME, Brækkan SK, Rosendaal FR, Frazer KA, Gran OV, Hansen J-B (2020) Fibrinogen gamma gene rs2066865 and risk of cancer-related venous thromboembolism, Haematologica 105(7) 1963
62.
Buijs JT, Versteeg HH (2020) Genes and proteins associated with the risk for cancer-associated thrombosis. Thromb Res 191:S43–S49PubMedCrossRef
63.
Unruh D, Horbinski C (2020) Beyond thrombosis: the impact of tissue factor signaling in cancer. J Hematol Oncol 13:1–14CrossRef
64.
Zhao X, Cheng C, Gou J, Yi T, Qian Y, Du X, Zhao X (2018) Expression of tissue factor in human cervical carcinoma tissue. Experimental Therapeutic Med 16(5):4075–4081
65.
Hassan N, Efing J, Kiesel L, Bendas G, Götte M (2023) The tissue factor pathway in Cancer: overview and role of Heparan Sulfate proteoglycans. Cancers 15(5):1524PubMedPubMedCentralCrossRef
66.
Xu C, Wang H, He H, Zheng F, Chen Y, Zhang J, Lin X, Ma D, Zhang H (2013) Low expression of TFPI-2 associated with poor survival outcome in patients with breast cancer. BMC Cancer 13(1):1–9CrossRef
67.
Stavik B, Skretting G, Sletten M, Sandset PM, Iversen N (2010) Overexpression of both TFPIα and TFPIβ induces apoptosis and expression of genes involved in the death receptor pathway in breast cancer cells. Mol Carcinog 49(11):951–963PubMedCrossRef
68.
Pihusch R, Danzl G, Scholz M, Harich D, Pihusch M, Lohse P, Hiller E (2002) Impact of thrombophilic gene mutations on thrombosis risk in patients with gastrointestinal carcinoma. Cancer 94(12):3120–3126PubMedCrossRef
69.
Heraudeau A, Delluc A, Le Henaff M, Lacut K, Leroyer C, Desrues B, Couturaud F, Tromeur C (2018) Risk of venous thromboembolism in association with factor V leiden in cancer patients–the EDITH case-control study. PLoS ONE 13(5):e0194973PubMedPubMedCentralCrossRef
70.
Liu Y, Liao X-W, Qin Y-Z, Mo X-W, Luo S-S (2020) Identification of F5 as a prognostic biomarker in patients with gastric cancer. Biomed Res Int 2020:1–13CrossRef
71.
Wahba MA, Ismail MA, Saad AA, Habashy DM, Hafeez ZMA, Boshnak NH (2015) Impact of thrombophilic genes mutations on thrombosis risk in Egyptian nonmetastatic cancer patients. Blood Coagul Fibrinolysis 26(3):309–315PubMedCrossRef
72.
Ording AG, Skjøth F, Søgaard M, Højen AA, Overvad TF, Noble S, Goldhaber SZ, Larsen TB (2021) Increasing incidence and declining mortality after cancer-associated venous thromboembolism: a nationwide cohort study. Am J Med 134(7):868–876e5PubMedCrossRef
Metadata
Title
Haemostatic gene variations in cervical cancer-associated venous thrombosis: considerations for clinical strategies
Authors
Beatriz Vieira Neto
Valéria Tavares
José Brito da Silva
Joana Liz-Pimenta
Inês Soares Marques
Lurdes Salgado
Luísa Carvalho
Deolinda Pereira
Rui Medeiros
Publication date
20-04-2024
Publisher
Springer US
Published in
Journal of Thrombosis and Thrombolysis
Print ISSN: 0929-5305
Electronic ISSN: 1573-742X
DOI
https://doi.org/10.1007/s11239-024-02983-2
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