Study of the association between HIF1A and VEGFA gene polymorphisms and ovarian cancer risk in women from Bashkortostan

Background. The major candidate genes for ovarian cancer (BRCA1/2) explain no more than 15–20 % of cases; therefore it is important to focus on the search for new molecular genetic markers. The aim of the study was to analyze the association of rs11549465/HIF1A, rs3025039/VEGFA, and rs2146323/VEGFA polymorphic variants with the risk of developing ovarian cancer in women from the Republic of Bashkortostan. Material and methods. Our research included DNA samples of women with ovarian cancer (n=205) and women without cancer at the time of blood sampling (n=259) from the Republic of Bashkortostan. Genotyping was carried out using the Real Time PCR method based on TaqMan technology. Results. Polymorphic variants, such as rs11549465/HIF1A, rs3025039/VEGFA, and rs2146323/VEGFA were not associated with the risk of developing ovarian cancer in women of the Republic of Bashkortostan. However, the rs11549465/HIF1A polymorphic locus was significantly correlated with the grade of tumor cell differentiation, and the rs3025039/VEGFA was associated with lymph node metastasis. Conclusion. These polymorphic variants may be associated with ovarian cancer prognosis. to confirm this association, it is necessary to conduct research on a large sample size.

1. Ferlay J., Ervik M., Lam F., Laversanne M., Colombet M., Mery L., Piñeros M., Znaor A., Soerjomataram I., Bray F. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer, 2024. [cited 2024 May 9]. URL: https://gco.iarc.who.int/today.

2. Ovarian cancer. Basisc and clinical research. Ed. by N.E. Kushlinsky, L.F. Gulyaeva, N.A. Ognerubov, I.S. Stilidi. Moscow, 2021. 752 p. (in Russian).

3. Demidova I.A. The characteristics of determination of BRCA1 and BRCA2 mutations in serous ovarian cancer. Modern Oncology. 2017; 19(1): 30–33. (in Russian). doi: 10.26442/1815-1434_19.1.30-33. EDN: ZBKNAP.

4. Telarovic I., Wenger R.H., Pruschy M. Interfering with Tumor Hypoxia for Radiotherapy Optimization. J Exp Clin Cancer Res. 2021; 40(1): 197. doi: 10.1186/s13046-021-02000-x.

5. Ioskevich M.S., Shtabinskaja T.T., Basinskij V.A. The significance of hif-1α, VEGF-A and iNOS in colon carcinogenesis. Hepatology and Gastroenterology. 2019; 3(1): 81–86. (in Russian). doi: 10.25298/2616-5546-2019-3-1-81-86. EDN: SDGJDE.

6. Samoylenko E.S., Kolesnlkova N.V., Baklay V.I., Maydannlkova E.Yu., Omelchenko E.V. VEGF gene polymorphism in complicated infective endocarditis. Russian Journal of Infection and Immunity. 2022; 12(5): 938–46. (in Russian). doi: 10.15789/2220-7619-VGP-1877. EDN: KNTFFN.

7. Uslu C., Tüz M., Yasan H., Okur E. Investigation of GLUT1, HIF1α and TBX21 Gene Polymorphisms in Laryngeal Cancer. Turk Arch Otorhinolaryngol. 2018; 56(2): 70–74. doi: 10.5152/tao.2018.3177.

8. Steffensen K.D., Waldstrøm M., Brandslund I., Jakobsen A. The relationship of VEGF polymorphisms with serum VEGF levels and progression-free survival in patients with epithelial ovarian cancer. Gynecol Oncol. 2010; 117(1): 109–16. doi: 10.1016/j.ygyno.2009.11.011.

9. Sivaprasad S., Govardhan B., Harithakrishna R., Venkat Rao G., Pradeep R., Kunal B., Ramakrishna N., Anuradha S., Reddy D.N. Association of vascular endothelial growth factor (VEGF) gene polymorphism and increased serum VEGF concentration with pancreatic adenocarcinoma. Pancreatology. 2013; 13(3): 267–72. doi: 10.1016/j.pan.2013.02.006.

10. Sáenz-López P., Vazquez F., Cozar J.M., Carretero R., Garrido F., Ruiz-Cabello F. VEGF polymorphisms are not associated with an increased risk of developing renal cell carcinoma in Spanish population. Hum Immunol. 2013; 74(1): 98–103. doi: 10.1016/j.humimm.2012.10.014.

11. Mandal R.K., Yadav S.S., Panda A.K., Khattri S. Vascular endothelial growth factor 936 c>T polymorphism increased oral cancer risk: evidence from a meta-analysis. Genet Test Mol Biomarkers. 2013; 17(7): 543–7. doi: 10.1089/gtmb.2013.0020.

12. Li Z., Wang Y., Liu C., Wang Z., Wang D., Liang X., Tian J. Association between VEGF single nucleotide polymorphism and breast cancer in the Northern China Han population. Breast Cancer Res Treat. 2021; 186(1): 149–56. doi: 10.1007/s10549-020-06024-3.

13. Lose F., Nagle C.M., O’Mara T., Batra J., Bolton K.L., Song H., Ramus S.J., Gentry-Maharaj A., Menon U., Gayther S.A., Pharoah P.D., Kedda M.A., Spurdle A.B. Vascular endothelial growth factor gene polymorphisms and ovarian cancer survival. Gynecol Oncol. 2010; 119(3): 479–83. doi: 10.1016/j.ygyno.2010.08.014.

14. Yamamoto Y., Kiyohara C., Ogata-Suetsugu S., Hamada N., Nakanishi Y. Association between genetic polymorphisms involved in the hypoxia-inducible factor pathway and lung cancer risk: a case-control study in Japan. Asia Pac J Clin Oncol. 2017; 13(3): 234–42. doi: 10.1111/ajco.12640.

15. Demirel H.S., Tasdemir P., Cetinkaya S., Cinar I., Kucukkartallar T., Dursun G. Colorectal Cancer Risk in Relation to Hypoxia Inducible Factor-1α (Hif-1 α) and Von Hippel-Lindau (Vhl) Gene Polymorphisms. Int J Hematol Oncol. 2017; 27(1): 13–20. doi: 10.4999/uhod.171674.

16. Meka P.B., Cingeetham A., Nanchari S.R., Damineni S., TipirisettiN., Gorre M., Jarjapu S., Annamaneni S., Digumarthi R., Satti V. HIF-1α (1772C>T) polymorphism as marker for breast cancer development. Tumour Biol. 2015; 36(5): 3215–20. doi: 10.1007/s13277-014-2949-y.

17. Li D., Liu J., Zhang W., Ren J., Yan L., Liu H., Xu Z. Association between HIF1A P582S and A588T polymorphisms and the risk of urinary cancers: a meta-analysis. PLoS One. 2013; 8(5). doi: 10.1371/journal.pone.0063445.

18. Li H.N., He T., Zha Y.J., Du F., Liu J., Lin H.R., Yang W.Z. HIF-1α rs11549465 C>T polymorphism contributes to increased cancer susceptibility: Evidence from 49 studies. J Cancer. 2019; 10(24): 5955–63. doi: 10.7150/jca.35716.

19. Barbitoff Y.A., Khmelkova D.N., Pomerantseva E.A., Slepchenkov A.V., Zubashenko N.A., Mironova I.V., Kaimonov V.S., Polev D.E., Tsay V.V., Glotov A.S., Aseev M.V., Shcherbak S.G., Glotov O.S., Isaev A.A., Predeus A.V. Expanding the Russian allele frequency reference via cross-laboratory data integration: insights from 7452 exome samples. Natl Sci Rev. 2024; 11(10). doi: 10.1093/nsr/nwae326.

20. Konac E., Onen H.I., Metindir J., Alp E., Biri A.A., Ekmekci A. An investigation of relationships between hypoxia-inducible factor-1 alpha gene polymorphisms and ovarian, cervical and endometrial cancers. Cancer Detect Prev. 2007; 31(2): 102–9. doi: 10.1016/j.cdp.2007.01.001.

21. Suzuki H., Yano M., Miyazawa M., Miyazawa M., Ogane N., Hasegawa K., Tsuda H., Yoshida M., Okagaki R., Ishihara O., Yasuda M. Association of the hypoxia-inducible factor-1α (HIF-1α) gene polymorphisms with prognosis in ovarian clear cell carcinoma. J Ovarian Res. 2019; 12(1): 7. doi: 10.1186/s13048-019-0481-9.

22. Li Y., Li C., Shi H., Lou L., Liu P. The association between the rs11549465 polymorphism in the hif-1α gene and cancer risk: a meta-analysis. Int J Clin Exp Med. 2015; 8(2): 1561–74.

23. Abakumova T.V., Gening S.O., Dolgova D.R., Gening T.P., Antoneeva I.I., Poludnyakova L.V., Kuznetsova T.I., Dergunova Yu.A., Panchenko E.G. The vascular endothelial growth factor in patients with advanced ovarian cancer on the background of chemotherapy according to the AP scheme. Clinical Laboratory Diagnostics. 2018; 63(9): 543–48. (in Russian). doi: 10.18821/0869-2084-2018-63-9-543-548. EDN: VNGYWL.

24. Bhaskari J., Premalata C.S., Shilpa V., Rahul B., Pallavi V.R., Ramesh G., Krishnamoorthy L. Vascular endothelial growth factor polymorphisms and a synchronized examination of plasma and tissue expression in epithelial ovarian cancers. Tumour Biol. 2016; 37(1): 1017–23. doi: 10.1007/s13277-015-3891-3.