Molecular Biology Reports

, Volume 38, Issue 8, pp 4955–4963 | Cite as

Cyclin D1 G870A polymorphism and breast cancer risk: a meta-analysis comprising 9,911 cases and 11,171 controls

  • Theodoros N. Sergentanis
  • Konstantinos P. Economopoulos


Cyclin D1 represents a key molecule in the regulation of cell cycle. CCND1 G870A (rs603965) polymorphism has drawn considerable attention as the A allele may generate a variant splice product with possible oncogenic actions. A meta-analysis examining the association between CCND1 G870A polymorphism and breast cancer risk was performed. Separate analyses on Caucasian and Chinese populations were also implemented. Eligible articles were identified for the period up to July 2010. Pooled odds ratios (OR) were appropriately derived from fixed-effects or random-effects models. Sensitivity analysis excluding studies whose genotype frequencies in controls significantly deviated from Hardy–Weinberg Equilibrium (HWE) was performed. Nine case–control studies on Caucasians (7,304 cases and 8,149 controls) and four case–control studies on Chinese (2,607 cases and 3,022 controls) were eligible. At the overall analysis the A allele seemed to be associated with elevated breast cancer risk; the effect seemed to be confined to homozygous carriers (pooled OR = 1.091, 95% CI: 1.008–1.179, P = 0.030, fixed effects) as heterozygous carriers did not exhibit significantly elevated breast cancer risk. No statistically significant associations were demonstrated in Caucasians. On the other hand, Chinese AA carriers exhibited marginally elevated breast cancer risk (pooled OR = 1.144, 95% CI: 0.984–1.329, P = 0.080, fixed effects). Nevertheless, the controls in two out of the four Chinese studies deviated from HWE. In conclusion, this meta-analysis suggests that the A allele of the CCND1 G870A polymorphism may confer additional breast cancer risk when it comes to homozygosity and Chinese populations. The need for additional, methodologically sound studies on Chinese populations seems warranted.


Cyclin D1 G870A Polymorphism Breast cancer Cell cycle 



None to report.

Conflicts of interest

The authors declare that there are no conflicts of interest.

Supplementary material

11033_2010_639_MOESM1_ESM.pdf (501 kb)
Supplementary material 1 (PDF 500 kb)


  1. 1.
    Knudsen KE, Diehl JA, Haiman CA, Knudsen ES (2006) Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 25:1620–1628PubMedCrossRefGoogle Scholar
  2. 2.
    Herber B, Truss M, Beato M, Muller R (1994) Inducible regulatory elements in the human cyclin D1 promoter. Oncogene 9:1295–1304PubMedGoogle Scholar
  3. 3.
    Sherr CJ (1993) Mammalian G1 cyclins. Cell 73:1059–1065PubMedCrossRefGoogle Scholar
  4. 4.
    Roy PG, Thompson AM (2006) Cyclin D1 and breast cancer. Breast 15:718–727PubMedCrossRefGoogle Scholar
  5. 5.
    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 18:4499–4508PubMedGoogle Scholar
  6. 6.
    Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ, Bernards R (1998) Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev 12:3488–3498PubMedCrossRefGoogle Scholar
  7. 7.
    Bigoni R, Negrini M, Veronese ML, Cuneo A, Castoldi GL, Croce CM (1996) Characterization of t(11;14) translocation in mantle cell lymphoma by fluorescent in situ hybridization. Oncogene 13:797–802PubMedGoogle Scholar
  8. 8.
    Simpson JF, Quan DE, O’Malley F, Odom-Maryon T, Clarke PE (1997) Amplification of CCND1 and expression of its protein product, cyclin D1, in ductal carcinoma in situ of the breast. Am J Pathol 151:161–168PubMedGoogle Scholar
  9. 9.
    Gillett CE, Lee AH, Millis RR, Barnes DM (1998) Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. J Pathol 184:396–400PubMedCrossRefGoogle Scholar
  10. 10.
    Dongsong N, Zhou JY (2010) FISH is more sensitive than southern analysis at identifying increased levels of cyclin D1 gene amplified in breast cancer cell lines. Mol Biol Rep 37:3473–3480PubMedCrossRefGoogle Scholar
  11. 11.
    Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WD, Heighway J (1995) Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11:1005–1011PubMedGoogle Scholar
  12. 12.
    Wu J, Wu SH, Bollig A, Thakur A, Liao DJ (2009) Identification of the cyclin D1b mRNA variant in mouse. Mol Biol Rep 36:953–957PubMedCrossRefGoogle Scholar
  13. 13.
    Lu F, Gladden AB, Diehl JA (2003) An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 63:7056–7061PubMedGoogle Scholar
  14. 14.
    Zhu Y, Wang J, He Q, Zhang JQ (2010) Association of p53 codon 72 polymorphism with prostate cancer: a meta-analysis. Mol Biol Rep. doi: 10.1007/s11033-010-0269-x Google Scholar
  15. 15.
    Li L, Huang X, Huo K (2010) IGFBP3 polymorphisms and risk of cancer: a meta-analysis. Mol Biol Rep 37:127–140PubMedCrossRefGoogle Scholar
  16. 16.
    Mao C, Liao RY, Qiu LX, Wang XW, Ding H, Chen Q (2010) BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep. doi: 10.1007/s11033-010-0351-4 Google Scholar
  17. 17.
    Liao RY, Mao C, Qiu LX, Ding H, Chen Q, Pan HF (2010) TGFBR1*6A/9A polymorphism and cancer risk: a meta-analysis of 13,662 cases and 14,147 controls. Mol Biol Rep 37:3227–3232PubMedCrossRefGoogle Scholar
  18. 18.
    Li C, Jiang Z, Liu X (2010) XPD Lys(751)Gln and Asp (312)Asn polymorphisms and bladder cancer risk: a meta-analysis. Mol Biol Rep 37:301–309PubMedCrossRefGoogle Scholar
  19. 19.
    Xu B, Niu XB, Wang ZD, Cheng W, Tong N, Mi YY, Min ZC, Tao J, Li PC, Zhang W, Wu HF, Zhang ZD, Wang ZJ, Hua LX, Feng NH, Wang XR (2010) IL-6-174G>C polymorphism and cancer risk: a meta-analysis involving 29,377 cases and 37,739 controls. Mol Biol Rep. doi: 10.1007/s11033-010-0399-1 Google Scholar
  20. 20.
    Zhu W, Wei BB, Shan X, Liu P (2010) 765G>C and 8473T>C polymorphisms of COX-2 and cancer risk: a meta-analysis based on 33 case–control studies. Mol Biol Rep 37:277–288PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang R, Xu G, Chen W, Zhang W (2010) Genetic polymorphisms of glutathione S-transferase M1 and bladder cancer risk: a meta-analysis of 26 studies. Mol Biol Rep. doi: 10.1007/s11033-010-0386-6 Google Scholar
  22. 22.
    Lu D, Yu X, Du Y (2010) Meta-analyses of the effect of cytochrome P450 2E1 gene polymorphism on the risk of head and neck cancer. Mol Biol Rep. doi: 10.1007/s11033-010-0375-9 Google Scholar
  23. 23.
    Qiu LX, Zhang J, Li WH, Zhang QL, Yu H, Wang BY, Wang LP, Wang JL, Wang HJ, Liu XJ, Luo ZG, Wu XH (2010) Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility. Mol Biol Rep. doi: 10.1007/s11033-010-0361-2 Google Scholar
  24. 24.
    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 17:2773–2781CrossRefGoogle Scholar
  25. 25.
    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 116:571–575PubMedCrossRefGoogle Scholar
  26. 26.
    Ceschi M, Sun CL, Van Den Berg D, Koh WP, Yu MC, 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 26:1457–1464PubMedCrossRefGoogle Scholar
  27. 27.
    Forsti 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 11:917–922PubMedGoogle Scholar
  28. 28.
    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 23:4257–4259PubMedGoogle Scholar
  29. 29.
    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 82:165–168PubMedCrossRefGoogle Scholar
  30. 30.
    Onay UV, Aaltonen K, Briollais L, Knight JA, Pabalan N, Kilpivaara O, Andrulis IL, Blomqvist C, Nevanlinna H, Ozcelik H (2008) Combined effect of CCND1 and COMT polymorphisms and increased breast cancer risk. BMC Cancer 8:6PubMedCrossRefGoogle Scholar
  31. 31.
    Shu XO, Moore DB, Cai Q, Cheng J, Wen W, Pierce L, Cai H, Gao YT, Zheng W (2005) Association of cyclin D1 genotype with breast cancer risk and survival. Cancer Epidemiol Biomark Prev 14:91–97Google Scholar
  32. 32.
    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 107:95–102PubMedCrossRefGoogle Scholar
  33. 33.
    Driver KE, Song H, Lesueur F, Ahmed S, Barbosa-Morais NL, Tyrer JP, Ponder BA, Easton DF, Pharoah PD, Dunning AM (2008) Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. Carcinogenesis 29:333–341PubMedCrossRefGoogle Scholar
  34. 34.
    Justenhoven C, Pierl CB, Haas S, Fischer HP, Hamann U, Baisch C, Harth V, Spickenheuer A, Rabstein S, Vollmert C, Illig T, Pesch B, Bruning T, Dippon J, Ko YD, Brauch H (2009) Polymorphic loci of E2F2, CCND1 and CCND3 are associated with HER2 status of breast tumors. Int J Cancer 124:2077–2081PubMedCrossRefGoogle Scholar
  35. 35.
    Millar EK, Dean JL, McNeil CM, O’Toole SA, Henshall SM, Tran T, Lin J, Quong A, Comstock CE, Witkiewicz A, Musgrove EA, Rui H, Lemarchand L, Setiawan VW, Haiman CA, Knudsen KE, Sutherland RL, Knudsen ES (2009) Cyclin D1b protein expression in breast cancer is independent of cyclin D1a and associated with poor disease outcome. Oncogene 28:1812–1820PubMedCrossRefGoogle Scholar
  36. 36.
    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 55:87–95PubMedGoogle Scholar
  37. 37.
    Yaylim-Eraltan I, Ergen A, Gormus U, Arikan S, Kucucuk S, Sahin O, Yigit N, Yildiz Y, Isbir T (2009) Breast cancer and cyclin D1 gene polymorphism in Turkish women. In Vivo 23:767–772PubMedGoogle Scholar
  38. 38.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–e34PubMedCrossRefGoogle Scholar
  39. 39.
    Economopoulos KP, Sergentanis TN (2010) GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: a comprehensive meta-analysis. Eur J Cancer 46:1617–1631PubMedCrossRefGoogle Scholar
  40. 40.
    Economopoulos KP, Sergentanis TN (2010) Three polymorphisms in cytochrome P450 1B1 (CYP1B1) gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 122:545–551PubMedCrossRefGoogle Scholar
  41. 41.
    Economopoulos KP, Sergentanis TN (2010) XRCC3 Thr241Met polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 121:439–443PubMedCrossRefGoogle Scholar
  42. 42.
    Economopoulos KP, Sergentanis TN (2010) Differential effects of MDM2 SNP309 polymorphism on breast cancer risk along with race: a meta-analysis. Breast Cancer Res Treat 120:211–216PubMedCrossRefGoogle Scholar
  43. 43.
    Sergentanis TN, Economopoulos KP (2010) Four polymorphisms in cytochrome P450 1A1 (CYP1A1) gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 122:459–469PubMedCrossRefGoogle Scholar
  44. 44.
    Sergentanis TN, Economopoulos KP (2010) GSTT1 and GSTP1 polymorphisms and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 121:195–202PubMedCrossRefGoogle Scholar
  45. 45.
    Sergentanis TN, Economopoulos KP (2010) Association of two CASP8 polymorphisms with breast cancer risk: a meta-analysis. Breast Cancer Res Treat 120:229–234PubMedCrossRefGoogle Scholar
  46. 46.
    Cavalli-Sforza LL, Piazza A, Menozzi P, Mountain J (1988) Reconstruction of human evolution: bringing together genetic, archaeological, and linguistic data. Proc Natl Acad Sci USA 85:6002–6006PubMedCrossRefGoogle Scholar
  47. 47.
    Cavalli-Sforza LL, Feldman MW (2003) The application of molecular genetic approaches to the study of human evolution. Nat Genet 33 Suppl:266–275PubMedCrossRefGoogle Scholar
  48. 48.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. Br Med J 327:557–560CrossRefGoogle Scholar
  49. 49.
    Higgins J, Green S (2008) Cochrane handbook for systematic reviews of interventions version 5.0.1. The Cochrane Collaboration. Accessed 31 May 2010
  50. 50.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Br Med J 315:629–634Google Scholar
  51. 51.
    Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J (2005) A method for meta-analysis of molecular association studies. Stat Med 24:1291–1306PubMedCrossRefGoogle Scholar
  52. 52.
    Rohlfs RV, Weir BS (2008) Distributions of Hardy–Weinberg equilibrium test statistics. Genetics 180:1609–1616PubMedCrossRefGoogle Scholar
  53. 53.
    Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover RN, Thomas G, Chanock SJ (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39:870–874PubMedCrossRefGoogle Scholar
  54. 54.
    Mavaddat N, Dunning AM, Ponder BA, Easton DF, Pharoah PD (2009) Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer. Cancer Epidemiol Biomark Prev 18:255–259CrossRefGoogle Scholar
  55. 55.
    Azzato EM, Driver KE, Lesueur F, Shah M, Greenberg D, Easton DF, Teschendorff AE, Caldas C, Caporaso NE, Pharoah PD (2008) Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort. Breast Cancer Res 10:R47PubMedCrossRefGoogle Scholar
  56. 56.
    Haiman CA, Garcia RR, Hsu C, Xia L, Ha H, Sheng X, Le Marchand L, Kolonel LN, Henderson BE, Stallcup MR, Greene GL, Press MF (2009) Screening and association testing of common coding variation in steroid hormone receptor co-activator and co-repressor genes in relation to breast cancer risk: the Multiethnic Cohort. BMC Cancer 9:43PubMedCrossRefGoogle Scholar
  57. 57.
    Onay VU, Briollais L, Knight JA, Shi E, Wang Y, Wells S, Li H, Rajendram I, Andrulis IL, Ozcelik H (2006) SNP–SNP interactions in breast cancer susceptibility. BMC Cancer 6:114PubMedCrossRefGoogle Scholar
  58. 58.
    Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309PubMedCrossRefGoogle Scholar
  59. 59.
    Yuan L, Gu X, Shao J, Wang M, Zhu Q, Zhang Z (2010) Cyclin D1 G870A polymorphism is associated with risk and clinicopathologic characteristics of bladder cancer. DNA Cell Biol 29:611–617PubMedCrossRefGoogle Scholar
  60. 60.
    Ni J, Wang M, Fu S, Zhou D, Zhang Z, Han S (2010) CCND1 G870A polymorphism and cervical cancer risk: a case–control study and meta-analysis. J Cancer Res Clin Oncol. doi: 10.1007/s00432-010-0904-x Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Theodoros N. Sergentanis
    • 1
    • 2
  • Konstantinos P. Economopoulos
    • 1
    • 2
  1. 1.School of MedicineNational University of AthensAthensGreece
  2. 2.Society of Junior DoctorsAthensGreece

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