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Association of CCND1 Gene c.870G>A Polymorphism with Breast Cancer Risk: A Case-ControlStudy and a Meta-Analysis

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Pathology & Oncology Research

Abstract

Cyclin D1 (CCND1) plays an essential role in regulating the progress of the cell cycle from G1 to S phase. There is a common c.870G>A polymorphism in the CCND1 gene. The aim of this study was to investigate the association of CCND1 gene c.870G>A polymorphism with breast cancer risk in a case-control study, which followed by a meta-analysis and an in silico analysis. Three hundred and thirty-five subjects composed of 174 women with breast cancer and 161 healthy controls were included in the case-control study. CCND1 gene c.870G>A genotyping was performed by PCR-RFLP. Meta-analysis was done for 14 studies composed of 7281 cases and 6820 controls. Some bioinformatics tools were applied to investigate the effects of c.870G>A on the mRNA splicing and structure. Our data obtained from case-control study revealed that GA genotype (OR: 1.89, 95%CI: 1.12–3.17, p = 0.017), AA genotype (OR: 1.95, 95%CI: 1.08–3.53, p = 0.027), and A allele (OR: 1.44, 95%CI: 1.06–1.95, p = 0.019) were significantly associated with breast cancer risk. The results of meta-analysis showed a significant association between CCND1 c.870G>A polymorphism and breast cancer risk, especially in Caucasian population. In silico analysis revealed that c.870G>A transition affect CCND1 mRNA splicing and secondary structure.

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References

  1. Makki J (2015) Diversity of breast carcinoma: histological subtypes and clinical relevance. Clin Med Insights Pathol 8:23–31

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fabris VT (2014) From chromosomal abnormalities to the identification of target genes in mouse models of breast cancer. Cancer Genet 207:233–246

    Article  CAS  PubMed  Google Scholar 

  3. Lee MM, Lin SS (2000) Dietary fat and breast cancer. Annu Rev Nutr 20:221–248

    Article  CAS  PubMed  Google Scholar 

  4. Strumylaitė L, Mechonošina K, Tamašauskas S (2010) Environmental factors and breast cancer. Medicina (Kaunas) 46:867–873

    Google Scholar 

  5. Theodoropoulos GE, Michalopoulos NV, Pantou MP, Kontogianni P, Gazouli M, Karantanos T, Lymperi M, Zografos G (2012) Caspase 9 promoter polymorphisms confer increased susceptibility to breast cancer. Cancer Genet 205:508–512

    Article  CAS  PubMed  Google Scholar 

  6. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11:558–572

    Article  CAS  PubMed  Google Scholar 

  7. Knudsen KE, Diehl JA, Haiman CA, Knudsen ES (2006) Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 25:1620–1628

    Article  CAS  PubMed  Google Scholar 

  8. Petre-Draviam CE, Williams EB, Burd CJ, Gladden A, Moghadam H, Meller J, Diehl JA, Knudsen KE (2005) A central domain of cyclin D1 mediates nuclear receptor corepressor activity. Oncogene 24:431–444

    Article  CAS  PubMed  Google Scholar 

  9. Kim KH, Roberts CW (2014) Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth. Cancer Genet 207:365–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WD, Heighway J (1995) Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11:1005–1011

    CAS  PubMed  Google Scholar 

  11. Wu Y, Fu H, Zhang H, Huang H, Chen M, Zhang L, Yang H, Qin D (2014) Cyclin D1 (CCND1) G870A polymorphisms and cervical cancer susceptibility: a meta-analysis based on ten case–control studies. Tumour Biol 35:6913–6918

    Article  CAS  PubMed  Google Scholar 

  12. Grieu F, Malaney S, Ward R, Joseph D, Iacopetta B (2003) Lack of association between CCND1 G870A polymorphism and the risk of breast and colorectal cancers. Anticancer Res 23:4257–4259

    CAS  PubMed  Google Scholar 

  13. Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, Paulweber B, Weitzer W, Leithner A, Samonigg H (2003) The 870G>A polymorphism of the cyclin D1 gene is not associated with breast cancer. Breast Cancer Res Treat 82:165–168

    Article  CAS  PubMed  Google Scholar 

  14. Försti A, Angelini S, Festa F, Sanyal S, Zhang Z, Grzybowska E, Pamula J, Pekala W, Zientek H, Hemminki K, Kumar R (2004) Single nucleotide polymorphisms in breast cancer. Oncol Rep 11:917–922

    PubMed  Google Scholar 

  15. Ceschi M, Sun CL, Van Den Berg D, Koh WP, MC Y, Probst-Hensch N (2005) The effect of cyclin D1 (CCND1) G870A-polymorphism on breast cancer risk is modified by oxidative stress among Chinese women in Singapore. Carcinogenesis 26:1457–1464

    Article  CAS  PubMed  Google Scholar 

  16. Shu XO, Moore DB, Cai Q, Cheng J, Wen W, Pierce L, Cai H, Gao Y, Zheng W (2005) Association of cyclin D1 genotype with breast cancer risk and survival. Cancer Epidemiol Biomark Prev 14:91–97

    CAS  Google Scholar 

  17. Onay UV, Aaltonen K, Briollais L, Knight JA, Pabalan N, Kilpivaara O, Andrulis I, Blomqvist C, Nevanlinna H, Ozcelik H (2008) Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk. BMC Cancer 8:6

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yu CP, Yu JC, Sun CA, Tzao C, Ho JY, Yen AM (2008) Tumor susceptibility and prognosis of breast cancer associated with the G870A polymorphism of CCND1. Breast Cancer Res Treat 107:95–102

    Article  CAS  PubMed  Google Scholar 

  19. Naidu R, Yip CH, Taib NA (2008) Polymorphisms of HER2 Ile655Val and cyclin D1 (CCND1) G870A are not associated with breast cancer risk but polymorphic allele of HER2 is associated with nodal metastases. Neoplasma 55:87–95

    CAS  PubMed  Google Scholar 

  20. Justenhoven C, Pierl CB, Haas S, Fischer HP, Hamann U, Baisch C, Harth V, Spickenheuer A, Rabstein S, Vollmert C, Illig T (2009) Polymorphic loci of E2F2, CCND1 and CCND3 are associated with HER2 status of breast tumors. Int J Cancer 124:2077–2081

    Article  CAS  PubMed  Google Scholar 

  21. Yaylim-Eraltan I, Ergen A, Görmüs U, Arikan S, Küçücük S, Sahin O, YİĞİT N, Yildiz Y, Isbir T (2009) Breast cancer and cyclin D1 gene polymorphism in Turkish women. In Vivo 23:767–772

    CAS  PubMed  Google Scholar 

  22. Jeon S, Choi JY, Lee KM, Park SK, Yoo KY, Noh DY, Ahn SH, Kang D (2010) Combined genetic effect of CDK7 and ESR1 polymorphisms on breast cancer. Breast Cancer Res Treat 121:737–742

    Article  CAS  PubMed  Google Scholar 

  23. Canbay E, Eraltan IY, Cercel A, Isbir T, Gazioglu E, Aydogan F, Cacina C, Cengiz A, Ferahman M, Zengin E, Unal H (2010) CCND1 and CDKN1B polymorphisms and risk of breast cancer. Anticancer Res 30:3093–3098

    CAS  PubMed  Google Scholar 

  24. Wasson MK, Chauhan PS, Singh LC, Katara D, Dev Sharma J, Zomawia E, Kataki A, Kapur S, Saxena S (2014) Association of DNA repair and cell cycle gene variations with breast cancer risk in northeast Indian population: a multiple interaction analysis. Tumour Biol 35:5885–5894

    Article  CAS  PubMed  Google Scholar 

  25. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mantel N, Haenszel W (1959) Statistical aspects of the analysisof data from retrospective studies of disease. J Natl Cancer Inst 22:719–748

    CAS  PubMed  Google Scholar 

  27. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  28. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  29. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang M, Marín A (2006) Characterization and prediction of alternative splice sites. Gene 366:219–227

    Article  CAS  PubMed  Google Scholar 

  31. Hebsgaard SM, Korning PG, Tolstrup N, Engelbrecht J, Rouzé P, Brunak S (1996) Splice site prediction in Arabidopsis thaliana DNA by combining local and global sequence information. Nucleic Acids Res 24:3439–3452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sabarinathan R, Tafer H, Seemann SE, Hofacker IL, Stadler PF, Gorodkin J (2013) The RNAsnp web server: predicting SNP effects on local RNA secondary structure. Nucleic Acids Res 41:W475–W479

    Article  PubMed  PubMed Central  Google Scholar 

  33. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:447–452

    Article  Google Scholar 

  34. Ormandy CJ, Musgrove EA, Hui R, Daly RJ (2003) Sutherland RL. Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res Treat 78:323–335

    Article  CAS  PubMed  Google Scholar 

  35. Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C, Barnes D, Peters G (1994) Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 54:1812–1817

    CAS  PubMed  Google Scholar 

  36. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7:812–821

    Article  CAS  PubMed  Google Scholar 

  37. Prall OW, Rogan EM, Musgrove EA, Watts CK, Sutherland RL (1998) C-Myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Mol Cell Biol 18:4499–4508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, DeFazio A, Watts CK, Musgrove EA, Sutherland RL (1993) Expression and amplification of cyclin genes in human breast cancer. Oncogene 8:2127–2133

    CAS  PubMed  Google Scholar 

  39. Lu C, Dong J, Ma H, Jin G, Hu Z, Peng Y, Guo X, Wang X, Shen H (2008) CCND1 G870A polymorphism contributes to breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 116:571–575

    Article  PubMed  Google Scholar 

  40. Sawa H, Ohshima TA, Ukita H, Murakami H, Chiba Y, Kamada H, Hara M, Saito I (1998) Alternatively spliced forms of cyclin D1 modulate entry into the cell cycle in an inverse manner. Oncogene 16:1701–1702

    Article  CAS  PubMed  Google Scholar 

  41. Weinstein IB, Begemann M, Zhou P, Han EK, Sgambato A, Doki Y, Arber N, Ciaparrone M, Yamamoto H (1997) Disorders in cell circuitry associated with multistage cacinogenesis: exploitable targets for cancer prevention and therapy. Clin Cancer Res 3:2696–2702

    CAS  PubMed  Google Scholar 

  42. Zhang J, Li Y, Wang R, Wen D, Sarbia M, Kuang G, Wu M, Wei L, He M, Zhang L, Wang S (2003) Association of cyclin D1 (G870A) polymorphism with susceptibility to esophageal and gastric cardiac carcinoma in a northern Chinese population. Int J Cancer 105:281–284

    Article  CAS  PubMed  Google Scholar 

  43. Howe D, Lynas C (2001) The cyclin D1 alternative transcripts [a] and [b] are expressed in normal and malignant lymphocytes and their relative levels are influenced by the polymorphism at codon 241. Haematologica 86:563–569

    CAS  PubMed  Google Scholar 

  44. Jamali S, Karimian M, Nikzad H, Aftabi Y (2016) The c. − 190 C>A transversion in promoter region of protamine1 gene as a genetic risk factor for idiopathic oligozoospermia. Mol Biol Rep 43:795–802

  45. Nikzad H, Karimian M, Sareban K, Khoshsokhan M, Hosseinzadeh Colagar A (2015) MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis. Reprod BioMed Online 31:668–680

    Article  CAS  PubMed  Google Scholar 

  46. Karimian M, Nikzad H, Tameh AA, Taherian A, Darvishi FZ, Haghighatnia MJ (2015) SPO11-C631T gene polymorphism: association with male infertility and an in silico-analysis. J Family Reprod Health 9:155–163

    PubMed  PubMed Central  Google Scholar 

  47. Karimian M, Hosseinzadeh Colagar A (2016) Methionine synthase A2756G transition might be a risk factor for male infertility: evidences from seven case-control studies. Mol Cell Endocrinol 425:1–10

    Article  CAS  PubMed  Google Scholar 

  48. Aftabi Y, Colagar AH, Mehrnejad F (2016) An in silico approach to investigate the source of the controversial interpretations about the phenotypic results of the human AhR-gene G1661A polymorphism. J Theor Biol 21(393):1–5

    Article  Google Scholar 

  49. Shen LX, Basilion JP, Stanton VP Jr (1999) Single-nucleotide polymorphisms can cause different structural folds of mRNA. Proc Natl Acad Sci U S A 96:7871–7876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang DG, Fan JB, Siao CJ, Berno A, Young P, Sapolsky R, Ghandour G, Perkins N, Winchester E, Spencer J, Kruglyak L (1998) Large-scale identification, mapping, and genotyping of single nucleotide polymorphisms in the human genome. Science 280:1077–1082

    Article  CAS  PubMed  Google Scholar 

  51. Pabalan N, Bapat B, Sung L, Jarjanazi H, Francisco-Pabalan O, Ozcelik H (2008) Cyclin D1 Pro241Pro (CCND1-G870A) polymorphism is associated with increased cancer risk in human populations: a meta-analysis. Cancer Epidemiol Biomark Prev 17:2773–2781

    Article  CAS  Google Scholar 

  52. Lu C, Dong J, Ma H, Jin G, Hu Z, Peng Y, Guo X, Wang X, Shen H (2009) CCND1 G870A polymorphism contributes to breast cancer susceptibility: a meta-analysis. Breast Cancer Res Treat 116:571–575

    Article  CAS  PubMed  Google Scholar 

  53. Cui J, Shen L, Wang Y (2012) Specific CCND1 G870A alleles associated with breast cancer susceptibility: a meta-analysis of 5,528 cases and 5,353 controls. Asian Pac J Cancer Prev 13:5023–5025

    Article  PubMed  Google Scholar 

  54. Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, Shi B (2015) Breast cancer intrinsic subtype classification, clinical use and future trends. Am J Cancer Res 5(10):2929

    PubMed  PubMed Central  Google Scholar 

  55. Perou CM (2011) Molecular stratification of triple-negative breast cancers. Oncologist 16(Supplement 1):61–70

    Article  PubMed  Google Scholar 

  56. Tobin NP, Sims AH, Lundgren KL, Lehn S, Landberg G (2011) Cyclin D1, Id1 and EMT in breast cancer. BMC Cancer 11(1):417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Arnold A, Papanikolaou A (2005) Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 23(18):4215–4224

    Article  CAS  PubMed  Google Scholar 

  58. Grillo M, Bott MJ, Khandke N, McGinnis JP, Miranda M, Meyyappan M, Rosfjord EC, Rabindran SK (2006) Validation of cyclin D1/CDK4 as an anticancer drug target in MCF-7 breast cancer cells: effect of regulated overexpression of cyclin D1 and siRNA-mediated inhibition of endogenous cyclin D1 and CDK4 expression. Breast Cancer Res Treat 95(2):185–194

    Article  CAS  PubMed  Google Scholar 

  59. Alao JP (2007) The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol Cancer 6(1):1

    Article  Google Scholar 

  60. Zang Y, Zhao S, Doll MA, Hein DW (2004) The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation. Pharmacogenet Genomics 14(11):717–723

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran

    Zahra Soleimani & Alireza Sharif

  2. Trauma Research Center, Kashan University of Medical Sciences, Kashan, Iran

    Davood Kheirkhah

  3. Department of Pediatrics, Kashan University of Medical Sciences, Kashan, Iran

    Davood Kheirkhah

  4. Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran

    Mohammad Reza Sharif

  5. Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran

    Mohammad Karimian

  6. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Younes Aftabi

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  1. Zahra Soleimani
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Correspondence to Davood Kheirkhah.

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Soleimani, Z., Kheirkhah, D., Sharif, M.R. et al. Association of CCND1 Gene c.870G>A Polymorphism with Breast Cancer Risk: A Case-ControlStudy and a Meta-Analysis. Pathol. Oncol. Res. 23, 621–631 (2017). https://doi.org/10.1007/s12253-016-0165-3

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