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rs15869 at miRNA binding site in BRCA2 is associated with breast cancer susceptibility

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Abstract

BRCA1 and BRCA2 mutations confer an increased lifetime risk of breast cancer; however, the associations of microRNA (miRNA) binding site single nucleotide polymorphisms (SNPs) in 3′ untranslated region (3′-UTR) of BRCA1 and BRCA2 with breast cancer (BC) risk were rarely reported. In this case–control study (498 BC patients and 498 matched controls), three SNPs (rs8176318, rs12516 and rs15869) were selected in the 3′-UTR of BRCA1 and BRCA2 genes, which were within miRNA-binding seed regions and might have potential function to regulate the expression of BRCA1/BRCA2. Unconditional logistic regression model was used to analyze the association between three SNPs and BC risk with adjustment of reproductive factors, and Student’s t test was performed to assess relative expression of BRCA2 in human breast cancer cell lines. Multifactor dimensionality reduction method was applied to calculate gene–reproductive factors interactions. A novel finding showed that AC [odds ratio (OR) 1.524; 95% confidence interval (CI) 1.141–2.035] genotype of rs15869 in BRCA2 could increase the risk of BC and recombinant plasmid-pGenesil-1-miR-627 could negatively regulate the expression of BRCA2 in MCF-7 and MDA-MB-231 cells. Gene–reproductive factors interactions analysis revealed that rs15869 together with age at menarche and number of pregnancy could increase the risk of BC by 2.39-fold and TT genotype (OR 0.316; 95% CI 0.130–0.767) of rs8176318 had a significant association with progesterone receptor status in BC patients. Our findings suggest that the miRNA-binding SNPs in BRCA1/BRCA2 and their interaction with reproductive factors might contribute to BC risk, and miR-627 might down-regulate BRCA2 expression in MCF-7 and MDA-MB-231 cells.

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References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86. doi:10.1002/ijc.29210.

    Article  CAS  PubMed  Google Scholar 

  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi:10.3322/caac.21262.

    Article  PubMed  Google Scholar 

  3. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32. doi:10.3322/caac.21338.

    Article  PubMed  Google Scholar 

  4. Fan L, Strasser-Weippl K, Li J-J, St Louis J, Finkelstein DM, Yu K-D, et al. Breast cancer in China. Lancet Oncol. 2014;15(7):e279–89. doi:10.1016/s1470-2045(13)70567-9.

    Article  PubMed  Google Scholar 

  5. Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Nat Cancer Inst. 2014;106(6):dju091. doi:10.1093/jnci/dju091.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sapkota Y. Germline DNA variations in breast cancer predisposition and prognosis: a systematic review of the literature. Cytogenet Genome Res. 2014;144(2):77–91. doi:10.1159/000369045.

    Article  CAS  PubMed  Google Scholar 

  7. Kurian AW. BRCA1 and BRCA2 mutations across race and ethnicity: distribution and clinical implications. Curr Opin Obstet Gynecol. 2010;22(1):72–8. doi:10.1097/GCO.0b013e328332dca3.

    Article  PubMed  Google Scholar 

  8. Moller P, Hagen AI, Apold J, Maehle L, Clark N, Fiane B, et al. Genetic epidemiology of BRCA mutations–family history detects less than 50% of the mutation carriers. Eur J Cancer. 2007;43(11):1713–7. doi:10.1016/j.ejca.2007.04.023.

    Article  PubMed  Google Scholar 

  9. Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304–11. doi:10.1200/JCO.2014.57.1414.

    Article  CAS  PubMed  Google Scholar 

  10. Hoberg-Vetti H, Bjorvatn C, Fiane BE, Aas T, Woie K, Espelid H, et al. BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study. Eur J Hum Genet EJHG. 2015;. doi:10.1038/ejhg.2015.196.

    PubMed  Google Scholar 

  11. Schwartz MD, Lerman C, Brogan B, Peshkin BN, Halbert CH, DeMarco T, et al. Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol. 2004;22(10):1823–9. doi:10.1200/JCO.2004.04.086.

    Article  PubMed  Google Scholar 

  12. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101(2):80–7. doi:10.1093/jnci/djn442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Brewster BL, Rossiello F, French JD, Edwards SL, Wong M, Wronski A, et al. Identification of fifteen novel germline variants in the BRCA1 3′UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site. Hum Mutat. 2012;33(12):1665–75. doi:10.1002/humu.22159.

    Article  CAS  PubMed  Google Scholar 

  14. Chatterjee S, Pal JK. Role of 5′- and 3′-untranslated regions of mRNAs in human diseases. Biol Cell. 2009;101(5):251–62. doi:10.1042/BC20080104.

    Article  CAS  PubMed  Google Scholar 

  15. Mishra PJ, Mishra PJ, Banerjee D, Bertino JR. MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics. Cell Cycle. 2008;7(7):853–8.

    Article  CAS  PubMed  Google Scholar 

  16. Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E. The role of site accessibility in microRNA target recognition. Nat Genet. 2007;39(10):1278–84. doi:10.1038/ng2135.

    Article  CAS  PubMed  Google Scholar 

  17. Landi D, Moreno V, Guino E, Vodicka P, Pardini B, Naccarati A, et al. Polymorphisms affecting micro-RNA regulation and associated with the risk of dietary-related cancers: a review from the literature and new evidence for a functional role of rs17281995 (CD86) and rs1051690 (INSR), previously associated with colorectal cancer. Mutat Res. 2011;717(1–2):109–15. doi:10.1016/j.mrfmmm.2010.10.002.

    Article  CAS  PubMed  Google Scholar 

  18. Wang S, Tao G, Wu D, Zhu H, Gao Y, Tan Y, et al. A functional polymorphism in MIR196A2 is associated with risk and prognosis of gastric cancer. Mol Carcinog. 2013;52(Suppl 1):E87–95. doi:10.1002/mc.22017.

    Article  CAS  PubMed  Google Scholar 

  19. Becher H, Schmidt S, Chang-Claude J. Reproductive factors and familial predisposition for breast cancer by age 50 years. A case–control-family study for assessing main effects and possible gene-environment interaction. Int J Epidemiol. 2003;32(1):38–48. doi:10.1093/ije/dyg003.

    Article  PubMed  Google Scholar 

  20. Andrieu N, Prevost T, Rohan T, Luporsi E, Le MG, Gerber M, et al. Variation in the interaction between familial and reproductive factors on the risk of breast cancer according to age, menopausal status, and degree of familiality. Int J Epidemiol. 2000;29(2):214–23. doi:10.1093/ije/29.2.214.

    Article  CAS  PubMed  Google Scholar 

  21. Metcalfe K, Gershman S, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2011;104(9):1384–92. doi:10.1038/bjc.2011.120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Metcalfe K, Lubinski J, Lynch HT, Ghadirian P, Foulkes WD, Kim-Sing C, et al. Family history of cancer and cancer risks in women with BRCA1 or BRCA2 mutations. J Natl Cancer Inst. 2010;102(24):1874–8. doi:10.1093/jnci/djq443.

    Article  CAS  PubMed  Google Scholar 

  23. Scully R, Livingston DM. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature. 2000;408(6811):429–32. doi:10.1038/35044000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Savage KI, Harkin DP. BRCA1, a ‘complex’ protein involved in the maintenance of genomic stability. FEBS J. 2015;282(4):630–46. doi:10.1111/febs.13150.

    Article  CAS  PubMed  Google Scholar 

  25. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2012;12(1):68–78. doi:10.1038/nrc3181.

    Article  CAS  Google Scholar 

  26. Fackenthal JD, Olopade OI. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer. 2007;7(12):937–48. doi:10.1038/nrc2054.

    Article  CAS  PubMed  Google Scholar 

  27. Zhou X, Xu X, Wang J, Lin J, Chen W. Identifying miRNA/mRNA negative regulation pairs in colorectal cancer. Sci Rep. 2015;5:12995. doi:10.1038/srep12995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Salim H, Akbar NS, Zong D, Vaculova AH, Lewensohn R, Moshfegh A, et al. miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence. Br J Cancer. 2012;107(8):1361–73. doi:10.1038/bjc.2012.382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Subramani A, Alsidawi S, Jagannathan S, Sumita K, Sasaki AT, Aronow B, et al. The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis. Sci Rep. 2013;3:2392. doi:10.1038/srep02392.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chen X, Xu Y, Cao X, Chen Y, Jiang J, Wang K. Associations of Il-1 family-related polymorphisms with gastric cancer risk and the role of Mir-197 In Il-1f5 expression. Medicine. 2015;94(47):e1982. doi:10.1097/MD.0000000000001982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ding L, Jiang Z, Chen Q, Qin R, Fang Y, Li H. A functional variant at miR-520a binding site in PIK3CA alters susceptibility to colorectal cancer in a Chinese Han population. BioMed Res Int. 2015;2015:373252. doi:10.1155/2015/373252.

    PubMed  PubMed Central  Google Scholar 

  32. Ma J, Guo R, Wang T, Pan X, Lei X. Let-7b binding site polymorphism in the B-cell lymphoma-extra large 3′UTR is associated with fluorouracil resistance of hepatocellular carcinoma. Mol Med Rep. 2015;11(1):677–81. doi:10.3892/mmr.2014.2692.

    CAS  PubMed  Google Scholar 

  33. Pelletier C, Speed WC, Paranjape T, Keane K, Blitzblau R, Hollestelle A, et al. Rare BRCA1 haplotypes including 3′UTR SNPs associated with breast cancer risk. Cell Cycle. 2014;10(1):90–9. doi:10.4161/cc.10.1.14359.

    Article  Google Scholar 

  34. Dorairaj JJ, Salzman DW, Wall D, Rounds T, Preskill C, Sullivan CA, et al. A germline mutation in the BRCA1 3′UTR predicts Stage IV breast cancer. BMC Cancer. 2014;14:421. doi:10.1186/1471-2407-14-421.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Figueiredo JC, Brooks JD, Conti DV, Poynter JN, Teraoka SN, Malone KE, et al. Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status. Breast Cancer Res Treat. 2011;127(3):819–29. doi:10.1007/s10549-010-1285-1.

    Article  CAS  PubMed  Google Scholar 

  36. Erturk E, Cecener G, Polatkan V, Gokgoz S, Egeli U, Tunca B, et al. Evaluation of genetic variations in miRNA-binding sites of BRCA1 and BRCA2 genes as risk factors for the development of early-onset and/or familial breast cancer. Asian Pac J Cancer Prev. 2014;15(19):8319–24. doi:10.7314/apjcp.2014.15.19.8319.

    Article  PubMed  Google Scholar 

  37. Zbuk K, Xie C, Young R, Heydarpour M, Pare G, Davis AD, et al. BRCA2 variants and cardiovascular disease in a multi-ethnic study. BMC Med Genet. 2012;13:56. doi:10.1186/1471-2350-13-56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Alanazi M, Reddy NP, Shaik JP, Ajaj SA, Jafari AA, Saeed H, et al. Association of BRCA2 variants with cardiovascular disease in Saudi Arabia. Genet Mol Res GMR. 2014;13(2):3876–84. doi:10.4238/2014.May.16.13.

    Article  CAS  PubMed  Google Scholar 

  39. Huang L, Wu C, Yu D, Wang C, Che X, Miao X, et al. Identification of common variants in BRCA2 and MAP2K4 for susceptibility to sporadic pancreatic cancer. Carcinogenesis. 2013;34(5):1001–5. doi:10.1093/carcin/bgt004.

    Article  CAS  PubMed  Google Scholar 

  40. Liu H, Gao F, Dahlstrom KR, Li G, Sturgis EM, Zevallos JP, et al. A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck. Tumour Biol. 2015;. doi:10.1007/s13277-015-4682-6.

    Google Scholar 

  41. Milne RL, Gaudet MM, Spurdle AB, Fasching PA, Couch FJ, Benitez J, et al. Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case–control study. Breast Cancer Res BCR. 2010;12(6):R110. doi:10.1186/bcr2797.

    Article  PubMed  Google Scholar 

  42. Campa D, Kaaks R, Le Marchand L, Haiman CA, Travis RC, Berg CD, et al. Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst. 2011;103(16):1252–63. doi:10.1093/jnci/djr265.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26(26):4282–8. doi:10.1200/JCO.2008.16.6231.

    Article  PubMed  Google Scholar 

  44. Sanford RA, Song J, Gutierrez-Barrera AM, Profato J, Woodson A, Litton JK, et al. High incidence of germline BRCA mutation in patients with ER low-positive/PR low-positive/HER-2 neu negative tumors. Cancer. 2015;121(19):3422–7. doi:10.1002/cncr.29572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dai X, Chen A, Bai Z. Integrative investigation on breast cancer in ER, PR and HER2-defined subgroups using mRNA and miRNA expression profiling. Sci Rep. 2014;4:6566. doi:10.1038/srep06566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81202278) and Medical Science and Technology Key Projects of Henan Province (201303005 and 20150374).

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    Authors and Affiliations

    1. Department of Epidemiology and Statistics, College of Public health, Zhengzhou University, Zhengzhou, 450001, Henan Province, People’s Republic of China

      Jingjing Cao, Rui Yan, Rui Peng, Kaijuan Wang, Peng Wang, Hua Ye & Chunhua Song

    2. Henan Key Laboratory of Tumor Epidemiology, Zhengzhou, 450001, Henan, People’s Republic of China

      Kaijuan Wang, Peng Wang, Hua Ye & Chunhua Song

    3. Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, 79968, USA

      Chenglin Luo

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    Jingjing Cao and Chenglin Luo contributed equally to this work and should be considered as co-first authors.

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    Cao, J., Luo, C., Yan, R. et al. rs15869 at miRNA binding site in BRCA2 is associated with breast cancer susceptibility. Med Oncol 33, 135 (2016). https://doi.org/10.1007/s12032-016-0849-2

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