2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2022-8-2-0-42743Genetics<strong>The role of highly penetrant mutations in <em>BRCA1</em> and <em>CHEK2</em> genes in the pattern of associations of matrix metalloproteinase gene polymorphisms with breast cancer</strong><strong>The role of highly penetrant mutations in <em>BRCA1</em> and <em>CHEK2</em> genes in the pattern of associations of matrix metalloproteinase gene polymorphisms with breast cancer</strong>PavlovaNadezhda V.PavlovaNadezhda V.doc.ss@mail.ruOrlovaValentina S.OrlovaValentina S.orlova@bsu.edu.ruBatlutskayaIrina V.BatlutskayaIrina V.bat@bsu.edu.ruEfremovaOlga A.EfremovaOlga A.efremova@bsu.edu.ruPonomarenkoIrina V.PonomarenkoIrina V.ponomarenko_i@bsu.edu.ru20228200

Background:&nbsp;Breast cancer (BC) is a malignant breast tumor, which occupies a leading place both in the structure of oncological diseases in women and among the causes of female mortality from malignant neoplasms. The role of genetic factors in the formation of breast cancer is beyond doubt. The aim of the study:&nbsp;To study the role of highly penetrant mutations in BRCA1 and CHEK2 genes in the pattern of associations of matrix metalloproteinase genes (MMP) polymorphism with BC. Materials and methods:&nbsp;To solve the research goal, the following three samples were formed: 26 BC patients with highly penetrant mutations in the BRCA1 (c.5266dup (5382insC), c.68_69del (185delAG), 2080delA) and CHEK2 (I157T)) genes, 332 BC patients without germinal mutations in the BRCA1 (c.5266dup (5382insC), c.68_69del (185delAG), 2080delA, 4153delA), BRCA2 (6174delT) and CHEK2 (I157T) genes and 746 women of the control group. Ten polymorphisms of five matrix metalloproteinase genes (MMP1, MMP2, MMP3, MMP8 and MMP9) were studied. The analysis of associations was carried out by the method of logistic regression. Results:&nbsp;The TT rs1940475 MMP8 genotype in BC patients with highly penetrant mutations in the BRCA1 and CHEK2 genes (3.84%) is 6-7 times less common in comparison with both patients without these mutations (22.80% pperm=0.04) and control group individuals (26.18% ORcov=0.11 95%CIcov 0.01-0.81 pperm=0.03). In BC patients who do not have highly penetrant mutations in the BRCA1 and CHEK2 genes, MMP9 gene polymorphisms are associated with the disease: rs17576 (ORcov=0.81 pperm=0.03), rs2250889 (ORcov=0.61-0.66 pperm=0.03), rs3787268 (ORcov=2.03 pperm=0.04) and nine different haplotypes of the six studied MMP9 loci (pperm&lt;0.05). Conclusion:&nbsp;The rs1940475 MMP8 polymorphic locus is associated with the risk of developing BC in women with highly penetrant mutations in the BRCA1 and CHEK2 genes, and polymorphisms of the MMP9 gene are associated with the disease in women without these mutations.

Background:&nbsp;Breast cancer (BC) is a malignant breast tumor, which occupies a leading place both in the structure of oncological diseases in women and among the causes of female mortality from malignant neoplasms. The role of genetic factors in the formation of breast cancer is beyond doubt. The aim of the study:&nbsp;To study the role of highly penetrant mutations in BRCA1 and CHEK2 genes in the pattern of associations of matrix metalloproteinase genes (MMP) polymorphism with BC. Materials and methods:&nbsp;To solve the research goal, the following three samples were formed: 26 BC patients with highly penetrant mutations in the BRCA1 (c.5266dup (5382insC), c.68_69del (185delAG), 2080delA) and CHEK2 (I157T)) genes, 332 BC patients without germinal mutations in the BRCA1 (c.5266dup (5382insC), c.68_69del (185delAG), 2080delA, 4153delA), BRCA2 (6174delT) and CHEK2 (I157T) genes and 746 women of the control group. Ten polymorphisms of five matrix metalloproteinase genes (MMP1, MMP2, MMP3, MMP8 and MMP9) were studied. The analysis of associations was carried out by the method of logistic regression. Results:&nbsp;The TT rs1940475 MMP8 genotype in BC patients with highly penetrant mutations in the BRCA1 and CHEK2 genes (3.84%) is 6-7 times less common in comparison with both patients without these mutations (22.80% pperm=0.04) and control group individuals (26.18% ORcov=0.11 95%CIcov 0.01-0.81 pperm=0.03). In BC patients who do not have highly penetrant mutations in the BRCA1 and CHEK2 genes, MMP9 gene polymorphisms are associated with the disease: rs17576 (ORcov=0.81 pperm=0.03), rs2250889 (ORcov=0.61-0.66 pperm=0.03), rs3787268 (ORcov=2.03 pperm=0.04) and nine different haplotypes of the six studied MMP9 loci (pperm&lt;0.05). Conclusion:&nbsp;The rs1940475 MMP8 polymorphic locus is associated with the risk of developing BC in women with highly penetrant mutations in the BRCA1 and CHEK2 genes, and polymorphisms of the MMP9 gene are associated with the disease in women without these mutations.

breast cancermatrix metalloproteinase genespolymorphismassociationsBRCA1CHEK2breast cancermatrix metalloproteinase genespolymorphismassociationsBRCA1CHEK2Список литературыGradishar WJ, Anderson BO, Blair SL, et al. Breast cancer version 3.2014. Journal of the National Comprehensive Cancer Network: JNCCN. 2014;12(4):542-590. DOI: https://doi.org/10.6004/jnccn.2014.0058Ferlay J, Colombet M, Soerjomataram I, et al. Cancer statistics for the year 2020: An overview. International Journal of Cancer. 2021;149:778-789. DOI: https://doi.org/10.1002/ijc.33588Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-A Cancer Journal for Clinicians. 2021;71(3):209-249. DOI: https://doi.org/10.3322/caac.21660Health care in Russia. 2021. Statistical compendium. Moscow: Rosstat; 2021. Russian.Kaprin AD, Starinsky VV, Petrova GV, editors. Malignant neoplasms in Russia in 2018 (morbidity and mortality). Moscow: MNIOI im. P.A. Gertsena &ndash; filial FGBU &laquo;NMITS radiologii&raquo; Minzdrava Rossii; 2019. Russian.Lilyquist J, Ruddy KJ, Vachon CM, et al. Common Genetic Variation and Breast Cancer Risk-Past, Present, and Future.&nbsp;Cancer Epidemiology Biomarkers and Prevention. 2018;27(4):380-394. DOI: https://doi.org/10.1158/1055-9965.EPI-17-1144Shiovitz S, Korde LA. Genetics of breast cancer: a topic in evolution.&nbsp;Annals of Oncology. 2015;26(7):1291-1299. DOI: https://doi.org/10.1093/annonc/mdv022Valova YV, Mingazheva ET, Prokofieva DS, et al. Ovarian cancer as part of hereditary cancer syndromes (review). Research Results in Biomedicine. 2021;7(4):330-362. Russian. DOI: https://doi.org/10.18413/2658-6533-2021-7-4-0-2Michailidou K, Lindstr&ouml;m S, Dennis J, et al. Association analysis identifies 65 new breast cancer risk loci.&nbsp;Nature. 2017;551(7678):92-94. DOI: https://doi.org/10.1038/nature24284Mucci LA, Hjelmborg JB, Harris JR, et al. Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA - Journal of the American Medical Association. 2016;315(1):68-76. DOI: https://doi.org/10.1001/jama.2015.17703Zhang H, Ahearn TU, Lecarpentier J, et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nature Genetics. 2020;52(6):572-581. DOI: https://doi.org/10.1038/s41588-020-0609-2Ahearn TU, Zhang H, Michailidou K, et al. Common variants in breast cancer risk loci predispose to distinct tumor subtypes. Breast Cancer Research. 2022;24(1):2. DOI: https://doi.org/10.1186/s13058-021-01484-xLee JY, Kim J, Kim SW, et al. BRCA1/2-negative, high-risk breast cancers (BRCAX) for Asian women: genetic susceptibility loci and their potential impacts. Scientific Reports. 2018;8(1):15263. DOI: https://doi.org/10.1038/s41598-018-31859-8Dofara SG, Chang SL, Diorio C. Gene Polymorphisms and Circulating Levels of MMP-2 and MMP-9: A Review of Their Role in Breast Cancer Risk. Anticancer Research. 2020;40(7):3619-3631. DOI: https://doi.org/10.21873/anticanres.14351Przybylowska 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 Research and Treatment. 2006;95(1):65-72. DOI: https://doi.org/10.1007/s10549-005-9042-6Radisky ES, Radisky DC. Matrix metalloproteinases as breast cancer drivers and therapeutic targets. Frontiers in Bioscience - Landmark. 2015;20(7):1144-1163. DOI: https://doi.org/10.2741/4364Eiro N, Gonzalez LO, Fraile M, et al. Breast Cancer Tumor Stroma: Cellular Components, Phenotypic Heterogeneity, Intercellular Communication, Prognostic Implications and Therapeutic Opportunities. Cancers. 2019;11(5):664. DOI: https://doi.org/10.3390/cancers11050664Baker EA, Stephenson TJ, Reed MWR, et al. Expression of proteinases and inhibitors in human breast cancer progression and survival. Molecular pathology : MP. 2002;55(5):300-304. DOI: https://doi.org/10.1136/mp.55.5.300McColgan 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. International Journal of Cancer. 2009;125(6):1473-8. DOI: https://doi.org/10.1002/ijc.24441Zhou P, Du LF, Lv GQ, 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 Research and Treatment. 2011;127(3):813-818. DOI: 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;7(2):e31251. DOI: https://doi.org/10.1371/journal.pone.0031251Białkowska 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. Hereditary Cancer in Clinical Practice. 2020;18:16. DOI: https://doi.org/10.1186/s13053-020-00147-wZhang X, Jin G, Li J, Zhang L. Association between four MMP-9 polymorphisms and breast cancer risk: a meta-analysis. Medical Science Monitor. 2015;21:1115-1123. DOI: 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;759:144972. DOI: 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. International Journal of Biological Markers. 2022;37(1):17246008221076145. DOI: https://doi.org/10.1177/17246008221076145Lei 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 Research and Treatment. 2007;103(1):61-69. DOI: https://doi.org/10.1007/s10549-006-9345-2Roehe AV, Frazzon APG, 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 Research and Treatment. 2007;102(1):123-124. DOI: https://doi.org/10.1007/s10549-006-9273-1Beeghly-Fadiel A, Lu W, Shu XO, et al. MMP9 polymorphisms and breast cancer risk: a report from the Shanghai Breast Cancer Genetics Study. Breast Cancer Research and Treatment. 2011;126(2):507-13. DOI: https://doi.org/10.1007/s10549-010-1119-1Shevchenko AV, Konenkov VI, Garbukov EIu, et al. 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. Voprosy onkologii. 2014;60(5):630-635. Russian. DOI: https://doi.org/10.37469/0507-3758-2014-60-5-630-635Churnosov MI, Altuchova OB, Demakova NA, et al. Associations of cytokines genetic variants with myomatous knots sizes. Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2014;5(6):1344-1347.Krivoshei IV, Altuchova OB, Golovchenko OV, et al. Genetic factors of hysteromyoma. Research Journal of Medical Sciences. 2015;9(4):182-185. DOI: https://doi.org/10.3923/rjmsci.2015.182.185Moskalenko MI, Ponomarenko IV, Polonikov AV, et al. Polymorphic locus rs652438 of the MMP12 gene is associated with the development of hypertension in women. Arterial Hypertension. 2019;25(1):60-65. Russian. DOI: https://doi.org/10.18705/1607-419X-2019-25-1-60-65Bushueva O, Solodilova M, Churnosov M, et al. The Flavin-Containing Monooxygenase 3 Gene and Essential Hypertension: The Joint Effect of Polymorphism E158K and Cigarette Smoking on Disease Susceptibility. International Journal of Hypertension. 2014:712169. DOI: https://doi.org/10.1155/2014/712169Golovchenko 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. European Journal of Obstetrics, Gynecology and Reproductive Biology. 2020;253:52-57. DOI: https://doi.org/10.1016/j.ejogrb.2020.07.045Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Research. 2016;44(D1):D877-D881. DOI: https://doi.org/10.1093/nar/gkv1340Ponomarenko IV, Polonikov AV, Churnosov MI. Association of ESR2 rs4986938 polymorphism with the development of endometrial hyperplasia. Obstetrics and Gynecology. 2019;4:66-72. Russian. DOI: https://dx.doi.org/10.18565/aig.2019.4.66-72Che R, Jack JR, Motsinger-Reif AA, et al. An adaptive permutation approach for genome-wide association study: evaluation and recommendations for use. BioData Mining. 2014;7:9. DOI: https://doi.org/10.1186/1756-0381-7-9Yarosh SL, Kokhtenko EV, Churnosov MI, et al. Joint effect of glutathione S-transferase genotypes and cigarette smoking on idiopathic male infertility. Andrologia. 2015;47(9):980-986. DOI: https://doi.org/10.1111/and.12367Polonikov A, Bykanova M, Ponomarenko I, et al. The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population. Clinical and Experimental Hypertension. 2017;39(4):306-311. DOI: https://doi.org/10.1080/10641963.2016.1246562GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318-1330. DOI: https://doi.org/10.1126/science.aaz1776Decock J, Long JR, Laxton RC, et al. Association of matrix metalloproteinase-8 gene variation with breast cancer prognosis. Cancer Research. 2007;67(21):10214-10221. DOI: https://doi.org/10.1158/0008-5472.CAN-07-1683Wang K, Zhou Y, Li G, et al. MMP8 and MMP9 gene polymorphisms were associated with breast cancer risk in a Chinese Han population. Scientific Reports. 2018;8(1):13422. DOI: https://doi.org/10.1038/s41598-018-31664-3Mavaddat N, Dunning AM, Ponder BA, et al. Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer. Cancer Epidemiology Biomarkers and Prevention. 2009;18(1):255-259. DOI: https://doi.org/10.1158/1055-9965.EPI-08-0704Pharoah PD, Tyrer J, Dunning AM, et al. Association between common variation in 120 candidate genes and breast cancer risk. PLoS Genetics. 2007;3(3):e42. DOI: https://doi.org/10.1371/journal.pgen.0030042Juurikka K, Butler GS, Salo T, et al. The Role of MMP8 in Cancer: A Systematic Review. International Journal of Molecular Sciences. 2019;20(18):4506. DOI: https://doi.org/10.3390/ijms20184506Moskalenko MI. The involvement of genes of matrix metalloproteinases in the development of arteial hypertension and its complication (review). Research Result. Medicine and Pharmacy. 2018;4(1):53-69. Russian. DOI: https://doi.org/10.18413/2313-8955-2018-4-1-53-69Chahil JK, Munretnam K, Samsudin N, et al. Genetic polymorphisms associated with breast cancer in malaysian cohort. Indian Journal of Clinical Biochemistry. 2015;30(2):134-9. DOI: https://doi.org/10.1007/s12291-013-0414-0Fu F, Wang C, Chen LM, et al. The influence of functional polymorphisms in matrix metalloproteinase 9 on survival of breast cancer patients in a Chinese population. DNA and Cell Biology. 2013;32(5):274-82. DOI: https://doi.org/10.1089/dna.2012.1928Al-Eitan LN, Jamous RI, Khasawneh RH. Candidate Gene Analysis of Breast Cancer in the Jordanian Population of Arab Descent: A Case-Control Study. Cancer Investigation. 2017;35(4):256-270. DOI: https://doi.org/10.1080/07357907.2017.1289217Slattery ML, 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;8:e63165. DOI: https://doi.org/10.1371/journal.pone.0063165Resler AJ, Malone KE, Johnson LG, et al. Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study. BMC Cancer. 2013;13:219. DOI: https://doi.org/10.1186/1471-2407-13-219Oliveira VA, Chagas DC, Amorim JR, et al. Association between matrix metalloproteinase-9 gene polymorphism and breast cancer in Brazilian women. Clinics. 2020;75:e1762. DOI: https://doi.org/10.6061/clinics/2020/e1762