Russian Journal of GeneticsRussian Journal of GeneticsГенетика0016-67583034-5103The Russian Academy of Sciences66689610.31857/S001667582302008XKYAYIZГЕНЕТИКА ЧЕЛОВЕКАAssociations of Polymorphic Loci of Matrix Metalloproteinase Genes with the Development of Breast Cancer in Women Central Chernozem Region of RussiaАссоциации полиморфных локусов генов матриксных металлопротеиназ с развитием рака молочной железы у женщин Центрально-Черноземного региона РоссииPavlovaN. V.ПавловаН. В.churnosov@bsu.edu.ruPonomarenkoI. V.ПономаренкоИ. В.churnosov@bsu.edu.ruOrlovaV. S.ОрловаВ. С.churnosov@bsu.edu.ruBatlutskayaI. V.БатлуцкаяИ. В.churnosov@bsu.edu.ruEfremovaO. A.ЕфремоваО. А.churnosov@bsu.edu.ruChurnosovM. I.ЧурносовМ. И.churnosov@bsu.edu.ruBelgorod State UniversityБелгородский государственный национальный исследовательский университет0102202359222623726022025Copyright ©; 2023, Н.В. Павлова, И.В. Пономаренко, В.С. Орлова, И.В. Батлуцкая, О.А. Ефремова, М.И. ЧурносовCopyright ©; 2023, Н.В. Павлова, И.В. Пономаренко, В.С. Орлова, И.В. Батлуцкая, О.А. Ефремова, М.И. Чурносов2023Н.В. Павлова, И.В. Пономаренко, В.С. Орлова, И.В. Батлуцкая, О.А. Ефремова, М.И. ЧурносовН.В. Павлова, И.В. Пономаренко, В.С. Орлова, И.В. Батлуцкая, О.А. Ефремова, М.И. Чурносовhttps://transsyst.ru/0016-6758/article/view/666896

The association of polymorphic variants of matrix metalloproteinase (MMP) genes with breast cancer (BC) in women of the Central Chernozem region of Russia, taking into account the presence/absence of a burdened family history, was studied. The study included 358 patients with breast cancer (68 patients had a burdened family history) and 746 women of the control group. Genotyping of 10 polymorphic loci of MMP genes (rs1799750 MMP1; rs243865 MMP2; rs679620 MMP3; rs1940475 MMP8; rs17576, rs17577, rs3918242, rs2250889, rs3787268, rs3918249 MMP9) was performed. To study the associations of polymorphic variants of MMP genes with breast cancer in two subgroups, taking into account the presence/absence of a burdened family history (the control group for these two subgroups was the same), the method of logistic regression analysis was used. It was revealed that a low risk of developing the disease among women with a burdened family history is associated with polymorphisms rs243865 MMP2 (OR = 0.53–0.54, pperm ≤ 0.03) and rs2250889 MMP9 (OR = 0.36–0.37, pperm ≤ 0.04). In women without burdened heredity, an increased risk of developing breast cancer is associated with rs3787268 MMP9 (OR = 2.16, pperm = 0.03) and haplotypes of polymorphic loci of the MMP9 gene (pperm ≤ 0.05): CA rs3918249–rs17576 (OR = 2.15), CCA rs3918242–rs3918249–rs17576 (OR = 1.69), CCAG rs3918242–rs3918249–rs17576–rs3787268 (OR = 1.69), CAGCG rs3918249–rs17576–rs3787268–rs2250889–rs17577 (OR = 3.06). Three haplotypes are associated with a low risk of breast cancer in women without burdened heredity: GG rs17576–rs3787268 (OR = 0.60), GGC rs17576–rs3787268–rs2250889 (OR = 0.63), and CGG rs3918249–rs17576–rs3787268 (OR = 0.62).

Изучена ассоциация полиморфных вариантов генов матриксных металлопротеиназ (MMP) с раком молочной железы (РМЖ) у женщин Центрально-Черноземного региона (ЦЧР) России с учетом наличия/отсутствия отягощенного семейного анамнеза. В исследование включены 358 больных РМЖ (у 68 пациенток зарегистрирован отягощенный семейный анамнез) и 746 женщин контрольной группы. Выполнено генотипирование 10 полиморфных локусов генов MMP (rs1799750 MMP1; rs243865 MMP2; rs679620 MMP3; rs1940475 MMP8; rs17576, rs17577, rs3918242, rs2250889, rs3787268, rs3918249 MMP9). Для изучения ассоциаций полиморфных вариантов ММР-генов с РМЖ в двух подгруппах с учетом наличия/отсутствия отягощенного семейного анамнеза (контрольная группа для этих двух подгрупп была одинаковая) использовался метод логистического регрессионного анализа. Выявлено, что низкий риск развития заболевания среди женщин с отягощенным семейным анамнезом ассоциирован с полиморфными локусами rs243865 MMP2 (ОШ = 0.53–0.54, pperm ≤ 0.03) и rs2250889 MMP9 (ОШ = 0.36–0.37, pperm ≤ 0.04). У женщин без отягощенной наследственности повышенный риск развития РМЖ ассоциирован с rs3787268 MMP9 (ОШ = 2.16, pperm = 0.03) и гаплотипами полиморфных локусов гена MMP9 (pperm ≤ 0.05): CA rs3918249–rs17576 (ОШ = 2.15), ССА rs3918242–rs3918249–rs17576 (ОШ = 1.69), ССAG rs3918242–rs3918249–rs17576-rs3787268 (ОШ = 1.69), CAGCG rs3918249–rs17576–rs3787268–rs2250889–rs17577 (ОШ = 3.06). Три гаплотипа ассоциированы с низким риском возникновения РМЖ у женщин без отягощенной наследственности: GG rs17576–rs3787268 (ОШ = 0.60), GGC rs17576–rs3787268–rs2250889 (ОШ = 0.63) и CGG rs3918249–rs17576–rs3787268 (ОШ = 0.62).

breast cancermatrix metalloproteinase genespolymorphic lociassociationhereditary burden.рак молочной железыгены матриксных металлопротеиназполиморфные локусыассоциациинаследственная отягощенностьGradishar W.J., Anderson B.O., Blair S.L. et al. Breast cancer version 3.2014 // J. Natl Compr. Canc. Netw. 2014. V. 12 (4). P. 542–590.Ferlay J., Colombet M., Soerjomataram I. et al. Cancer statistics for the year 2020: An overview // Int. J. Cancer. 2021. V. 149. P. 778–789. https://doi.org/10.1002/ijc.33588Sung H., Ferlay J., Siegel R.L. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries // CA Cancer J. Clin. 2021. V. 71. P. 209–249. https://doi.org/10.3322/caac.21660Здравоохранение в России. 2021: Стат.сб./Росстат. М., 2021. 171 с.Каприн А.Д., Старинский В.В., Петрова Г.В. Злокачественные новообразования в России в 2018 г. М., 2019. 250 с.Lilyquist J., Ruddy K.J., Vachon C.M., Couch F.J. Common genetic variation and breast cancer risk-past, present, and future // Cancer Epidemiol. Biomarkers Prev. 2018. V. 27 (4). P. 380–394. https://doi.org/10.1158/1055-9965.EPI-17-1144Shiovitz S., Korde L.A. Genetics of breast cancer: A topic in evolution // Ann. Oncol. 2015. V. 26 (7). P. 1291–1299. https://doi.org/10.1093/annonc/mdv022Валова Я.В., Мингажева Э.Т., Прокофьева Д.С. и др. Рак яичников в составе наследственных онкологических синдромов (обзор) // Науч. результаты биомед. исследований. 2021. Т. 7. № 4. С. 330–362. https://doi.org/10.18413/2658- 6533-2021-7-4-0-2https://www.ebi.ac.uk/gwas/search?query=breast% 20carcinomaMichailidou K., Lindström S., Dennis J. et al. Association analysis identifies 65 new breast cancer risk loci // Nature. 2017. V. 551(7678). P. 92–94. https://doi.org/10.1038/nature24284Mucci L.A., Hjelmborg J.B., Harris J.R. et al. Familial risk and heritability of cancer among twins in nordic countries // JAMA. 2016. V. 315(1). P. 68–76. https://doi.org/10.1001/jama.2015.17703Radisky E.S., Radisky D.C. Matrix metalloproteinases as breast cancer drivers and therapeutic targets // Front Biosci. (Landmark Ed). 2015. V. 20(7). P. 1144–1163. https://doi.org/10.2741/4364Eiro N., Gonzalez L.O., Fraile M. et al. Breast cancer tumor stroma: Cellular components, phenotypic heterogeneity, intercellular communication, prognostic implications and therapeutic opportunities // Cancers (Basel). 2019. V. 11 (5). P. 664. https://doi.org/10.3390/cancers11050664Baker E.A., Stephenson T.J., Reed M.W., Brown N.J. Expression of proteinases and inhibitors in human breast cancer progression and survival // Mol. Pathol. 2002. V. 55(5). P. 300–304. https://doi.org/10.1136/mp.55.5.300Przybylowska K., Kluczna A., Zadrozny M. et al. Polymorphisms of the promoter regions of matrix metalloproteinases genes MMP-1 and MMP-9 in breast cancer // Breast Cancer Res. Treat. 2006. V. 95(1). P. 65–72.McColgan P., Sharma P. Polymorphisms of matrix metalloproteinases 1, 2, 3 and 9 and susceptibility to lung, breast and colorectal cancer in over 30 000 subjects // Int. J. Cancer. 2009. V. 125 (6). P. 1473–1478. https://doi.org/10.1002/ijc.24441Zhou P., Du L.F., Lv G.Q. et al. Current evidence on the relationship between four polymorphisms in the matrix metalloproteinases (MMP) gene and breast cancer risk: A meta-analysis // Breast Cancer Res. Treat. 2011. V. 127 (3). P. 813–818. https://doi.org/10.1007/s10549-010-1294-0Liu D., Guo H., Li Y. et al. Association between polymorphisms in the promoter regions of matrix metalloproteinases (MMPs) and risk of cancer metastasis: A meta-analysis // PLoS One. 2012. V. 7 (2). P. e31251.Białkowska K., Marciniak W., Muszyńska M. et al. Polymorphisms in MMP-1, MMP-2, MMP-7, MMP-13 and MT2A do not contribute to breast, lung and colon cancer risk in polish population // Hered. Cancer Clin. Pract. 2020. V. 18. P. 16.Delgado-Enciso I., Cepeda-Lopez F.R., Monrroy-Guizar E.A. et al. Matrix metalloproteinase-2 promoter polymorphism is associated with breast cancer in a Mexican population // Gynecol. Obstet Investig. 2008. V. 65 (1). P. 68–72.Slattery M.L., John E., Torres-Mejia G. et al. Matrix metalloproteinase genes are associated with breast cancer risk and survival: The breast cancer health disparities study // PLoS One. 2013. V. 8. P. e63165. https://doi.org/10.1371/journal.pone.0063165Zhang X., Jin G., Li J., Zhang L. Association between four MMP-9 polymorphisms and breast cancer risk: A meta-analysis // Med. Sci. Monit. 2015. V. 21. P. 1115–1123. https://doi.org/10.12659/MSM.893890Xu T., Zhang S., Qiu D. et al. Association between matrix metalloproteinase 9 polymorphisms and breast cancer risk: An updated meta-analysis and trial sequential analysis // Gene. 2020. V. 759. P. 144972. https://doi.org/10.1016/j.gene.2020.144972Yan C., Sun C., Lu D. et al. Estimation of associations between MMP9 gene polymorphisms and breast cancer: Evidence from a meta-analysis // Int. J. Biol. Markers. 2022. P. 17246008221076145. https://doi.org/10.1177/17246008221076145Wang K., Zhou Y., Li G. et al. MMP8 and MMP9 gene polymorphisms were associated with breast cancer risk in a Chinese Han population // Sci. Rep. 2018. V. 8(1). P. 13422. https://doi.org/10.1038/s41598-018-31664-3Tikunova E., Ovtcharova V., Reshetnikov E. et al. Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia // Int. J. Ophthalmol. 2017. V. 10. P. 1490–1494. https://doi.org/10.18240/ijo.2017.10.02Reshetnikov E., Ponomarenko I., Golovchenko O. et al. The VNTR polymorphism of the endothelial nitric oxide synthase gene and blood pressure in women at the end of pregnancy // Taiwan J. Obstet Gynecol. 2019. V. 58(3). P. 390–395. https://doi.org/10.1016/j.tjog.2018.11.035Ward L.D., Kellis M. HaploReg v4: Systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease // Nucl. Acids Res. 2016. V. 44(D1). P. D877–D881. https://doi.org/10.1093/nar/gkv1340Ponomarenko I., Reshetnikov E., Polonikov A. et al. Candidate genes for age at menarche are associated with endometrial hyperplasia // Gene. 2020. V. 757. P. 144933. https://doi.org/10.1016/j.gene.2020.144933Reshetnikov E., Zarudskaya O., Polonikov A. et al. Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia // J. Obstet Gynaecol. Res. 2017. V. 43(7). P. 1139–1144. https://doi.org/10.1111/jog.13329Golovchenko O., Abramova M., Ponomarenko I. et al. Functionally significant polymorphisms of ESR1 and PGR and risk of intrauterine growth restriction in population of Central Russia // Eur. J. Obstet Gynecol. Reprod. Biol. 2020. V. 253. P. 52–57. https://doi.org/10.1016/j.ejogrb.2020.07.045Purcell S., Neale B., Todd-Brown K. et al. PLINK: A tool set for whole-genome association and population-based linkage analyses // Am. J. Hum. Genet. 2007. V. 81(3). P. 559–575. https://doi.org/10.1086/519795Ponomarenko I., Reshetnikov E., Polonikov A. et al. Candidate genes for age at menarche are associated with endometriosis // Reprod. Biomed. Online. 2020. V. 41(5). P. 943–956. https://doi.org/10.1016/j.rbmo.2020.04.016Che R., Jack J.R., Motsinger-Reif A.A., Brown C.C. An adaptive permutation approach for genome-wide association study: evaluation and recommendations for use // BioData Min. 2014. V. 7. P. 9. https://doi.org/10.1186/1756-0381-7-9Pers T.H., Karjalainen J.M., Chan Y. et al. Biological interpretation of genome-wide association studies using predicted gene functions // Nat. Commun. 2015. V. 6. P. 5890. https://doi.org/10.1038/ncomms6890Tak Y.G., Farnham P.J. Making sense of GWAS: Using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the human genome // Epigenetics & Chromatin. 2015. V. 8. P. 57. https://doi.org/10.1186/s13072-015-0050-4Ponomarenko I., Reshetnikov E., Polonikov A. et al. Candidate genes for age at menarche are associated with uterine leiomyoma // Front. Genet. 2021. V. 11. P. 512940. https://doi.org/10.3389/fgene.2020.512940Zhou Y., Yu C., Miao X. et al. Substantial reduction in risk of breast cancer associated with genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes // Carcinogenesis. 2004. V. 25(3). P. 399–404.Saeed H.M., Alanazi M.S., Alshahrani O. et al. Matrix metalloproteinase-2 C(−1306) T promoter polymorphism and breast cancer risk in the Saudi population // Acta Biochim. Pol. 2013. V. 60(3). P. 405–409.Yang L., Li N., Wang S. et al. Lack of association between the matrix metalloproteinase-2–1306C>T polymorphism and breast cancer susceptibility: A meta-analysis // Asian Pac. J. Cancer Prev. 2014. V. 15(12). P. 4823–4827.Néjima D.B., Zarkouna Y.B., Gammoudi A. et al. Prognostic impact of polymorphism of matrix metalloproteinase-2 and metalloproteinase tissue inhibitor-2 promoters in breast cancer in tunisia: case-control study // Tumour Biol. 2015. V. 36(5). P. 3815–3822. https://doi.org/10.1007/s13277-014-3023-5Habel A.F., Ghali R.M., Bouaziz H. et al. Common matrix metalloproteinase-2 gene variants and altered susceptibility to breast cancer and associated features in Tunisian women // Tumour Biol. 2019. V. 41(4). P. 1010428319845749. https://doi.org/10.1177/1010428319845749Lei H., Hemminki K., Altieri A. et al. Promoter polymorphisms in matrix metalloproteinases and their inhibitors: Few associations with breast cancer susceptibility and progression // Breast Cancer Res. Treat. 2007. V. 103(1). P. 61–69.Zagouri F., Sergentanis T.N., Gazouli M. et al. MMP-2 –1306C>T polymorphism in breast cancer: a case-control study in a south European population // Mol. Biol. Rep. 2013. V. 40(8). P. 5035–5040.Roehe A.V., Frazzon A.P., Agnes G. et al. Detection of polymorphisms in the promoters of matrix metalloproteinases 2 and 9 genes in breast cancer in South Brazil: preliminary results // Breast Cancer Res. Treat. 2007. V. 102. P. 123–124.Beeghly-Fadiel A., Lu W., Long J.R. et al. Matrix metalloproteinase-2 polymorphisms and breast cancer susceptibility // Cancer Epidemiol. Biomarkers Prev. 2009. V. 18(6). P. 1770–1776. https://doi.org/10.1158/1055-9965.EPI-09-0125Ledwoń J.K., Hennig E.E., Maryan N. et al. Common low-penetrance risk variants associated with breast cancer in Polish women // BMC Cancer. 2013. V. 13. P. 510. https://doi.org/10.1186/1471-2407-13-510Manshadi Z.D., Hamid M., Kosari F. et al. The relationship between matrix metalloproteinase gene polymorphisms and tumor type, tumor size, and metastasis in women with breast cancer in Central Iran // Middle East J. Cancer. 2018. V. 9 (2). P. 123–131.Ou Y.X., Bi R. Meta-analysis on the relationship between the SNP of MMP-2 –1306C>T and susceptibility to breast cancer // Eur. Rev. Med. Pharmacol. Sci. 2020. V. 24(3). P. 1264–1270. https://doi.org/10.26355/eurrev_202002_20181Shevchenko A.V., Konenkov V.I., Garbukov E.Iu., Stakheeva M.N. Associating of polymorphism in the promoter regions of genes of metalloproteinase (MMP2, MMP3, MMP9) with options of the clinical course of breast cancer in Russian women // Vopr. Onkol. 2014. V. 60(5). P. 630–635. Russian.Price S.J., Greaves D.R., Watkins H. Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: Role of Sp1 in allele-specific transcriptional regulation // J. Biol. Chem. 2001. V. 276(10). P. 7549–7558.Polonikov A., Rymarova L., Klyosova E. et al. Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease // J. Cell Biochem. 2019. V. 120(10). P. 16467–16482. https://doi.org/10.1002/jcb.28815Moskalenko M., Ponomarenko I., Reshetnikov E. et al. Polymorphisms of the matrix metalloproteinase genes are associated with essential hypertension in a Caucasian population of Central Russia // Sci. Rep. 2021. V. 11(1). P. 5224. https://doi.org/10.1038/s41598-021-84645-4Москаленко М.И. Вовлеченность генов матриксных металлопротеиназ в формирование артериальной гипертензии и ее осложнений (обзор) // Науч. результат. Медицина и фармация. 2018. Т. 4. № 1. С. 53–69. https://doi.org/10.18413/2313-8955- 2018-4-1-53-69Beeghly-Fadiel A., Lu W., Shu X.O. et al. MMP9 polymorphisms and breast cancer risk: A report from the shanghai breast cancer genetics study // Breast Cancer Res. Treat. 2011. V. 126(2). P. 507–513. https://doi.org/10.1007/s10549-010-1119-1Fu F., Wang C., Chen L.M. et al. The influence of functional polymorphisms in matrix metalloproteinase 9 on survival of breast cancer patients in a Chinese population // DNA Cell Biol. 2013. V. 32(5). P. 274–282. https://doi.org/10.1089/dna.2012.1928Chahil J.K., Munretnam K., Samsudin N. et al. Genetic polymorphisms associated with breast cancer in malaysian cohort // Indian J. Clin. Biochem. 2015. V. 30(2). P. 134–139. https://doi.org/10.1007/s12291-013-0414-0Al-Eitan L.N., Jamous R.I., Khasawneh R.H. Candidate gene analysis of breast cancer in the Jordanian population of arab descent: A case-control study // Cancer Invest. 2017. V. 35(4). P. 256–270. https://doi.org/10.1080/07357907.2017.1289217Dvornyk V., Liu X.H., Shen H. et al. Differentiation of Caucasians and Asians at bone mass candidate genes: Implication for ethnic difference of bone mass // Ann Hum. Genet. 2003. V. 67. P. 216–227.Pasutto F., Zenkel M., Hoja U. et al. Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1 // Nat. Commun. 2017. V. 8. P. 15466. https://doi.org/10.1038/ncomms15466Eliseeva N., Ponomarenko I., Reshetnikov E. et al. LOXL1 gene polymorphism candidates for exfoliation glaucoma are also associated with a risk for primary open-angle glaucoma in a Caucasian population from Central Russia // Mol. Vis. 2021. V. 27. P. 262–269.Starikova D., Ponomarenko I., Reshetnikov E. et al. Novel data about association of the functionally significant polymorphisms of the MMP-9 gene with exfoliation glaucoma in the Caucasian population of Central Russia // Ophthalmic. Res. 2021. V. 64(3). P. 458–464. https://doi.org/10.1159/000512507Minyaylo O., Ponomarenko I., Reshetnikov E. et al. Functionally significant polymorphisms of the MMP-9 gene are associated with peptic ulcer disease in the Caucasian population of Central Russia // Sci. Rep. 2021. V. 11(1). P. 13515. https://doi.org/10.1038/s41598-021-92527-yJones J.L., Walker R.A. Control of matrix metalloproteinase activity in cancer // J. Pathol. 1997. V. 183(4). P. 377–379.Song J., Su H., Zhou Y.Y., Guo L.L. Prognostic value of matrix metalloproteinase 9 expression in breast cancer patients: a meta-analysis // Asian Pac. J. Cancer Prev. 2013. V. 14(3). P. 1615–1621.Moskalenko M.I., Milanova S.N., Ponomarenko I.V. et al. Study of associations of polymorphism of matrix metalloproteinases genes with the development of arterial hypertension in men // Kardiologiia. 2019. V. 59(7S). P. 31–39. Russian. https://doi.org/10.18087/cardio.2598