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Association between a novel polymorphism (rs2046210) of the 6q25.1 locus and breast cancer risk

  • Epidemiology
  • Published:
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Abstract

The novel single nucleotide polymorphism (SNP), rs2046210, was identified in a breast cancer genome-wide association study of Chinese women. The SNP is located on 6q25.1 in proximity to the C6orf97 and estrogen receptor 1 (ESR1) genes. To replicate this susceptibility, a number of case–control studies have been conducted in various populations. However, some results were inconclusive due to the restriction of sample size or ethnic diversity. To derive a more precise estimation of the relationship between rs2046210 and genetic risk of breast cancer, we performed the first comprehensive meta-analysis which included 121,494 cases and 119,295 controls from 14 published studies. Overall, significant increased risk between the A allele of rs2046210 and breast cancer was found in the total population (allelic model: OR = 1.16, 95 %CI = 1.11–1.21, P heterogeneity < 0.0001; dominant model: OR = 1.22, 95 %CI = 1.14–1.29, P heterogeneity < 0.0001; recessive model: OR = 1.21, 95 %CI = 1.13–1.29, P heterogeneity < 0.0001). When stratified by ethnicity, significant elevated risk was found among Europeans and Asians. However, no significant association was detected in African descent population. In the subgroup analyses according to estrogen receptor (ER) positive/negative status, our results suggested that this polymorphism tended to increase breast cancer risk in ER negative tumors by a greater magnitude compared to ER positive tumors. In addition, our subgroup analysis also indicated that this SNP was significantly associated with the risk of breast cancer for BRCA1 mutation carriers and exhibited weaker association with the risk for BRCA2 mutation carriers. Substantial heterogeneity was present in the overall analysis, but largely disappeared after stratification by ethnicity. Despite some limitations, this meta-analysis demonstrates that the rs2046210 polymorphism may be a risk factor associated with increased breast cancer risk. However, the association varies in different ethnicities.

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References

  1. Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33(Suppl):238–244

    Article  PubMed  CAS  Google Scholar 

  2. Nathanson KL, Wooster R, Weber BL (2001) Breast cancer genetics: what we know and what we need. Nat Med 7(5):552–556

    Article  PubMed  CAS  Google Scholar 

  3. Peto J, Collins N, Barfoot R, Seal S, Warren W et al (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91(11):943–949

    Article  PubMed  CAS  Google Scholar 

  4. Pharoah PD, Dunning AM, Ponder BA, Easton DF (2004) Association studies for finding cancer-susceptibility genetic variants. Nat Rev Cancer 4(11):850–860

    Article  PubMed  CAS  Google Scholar 

  5. Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK et al (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41(5):585–590

    Article  PubMed  CAS  Google Scholar 

  6. Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R et al (2010) A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 42(10):885–892

    Article  PubMed  CAS  Google Scholar 

  7. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093

    Article  PubMed  CAS  Google Scholar 

  8. Fletcher O, Johnson N, Orr N, Hosking FJ, Gibson LJ et al (2011) Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst 103(5):425–435

    Article  PubMed  CAS  Google Scholar 

  9. Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39(7):870–874

    Article  PubMed  CAS  Google Scholar 

  10. Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39(7):865–869

    Article  PubMed  CAS  Google Scholar 

  11. Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40(6):703–706

    Article  PubMed  CAS  Google Scholar 

  12. Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S et al (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41(5):579–584

    Article  PubMed  CAS  Google Scholar 

  13. Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A et al (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42(6):504–507

    Article  PubMed  CAS  Google Scholar 

  14. Zheng W, Long J, Gao YT, Li C, Zheng Y et al (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41(3):324–328

    Article  PubMed  CAS  Google Scholar 

  15. Figtree GA, Noonan JE, Bhindi R, Collins P (2009) Estrogen receptor polymorphisms: significance to human physiology, disease and therapy. Recent Pat DNA Gene Seq 3(3):164–171

    Article  PubMed  CAS  Google Scholar 

  16. Dunning AM, Healey CS, Baynes C, Maia AT, Scollen S et al (2009) Association of ESR1 gene tagging SNPs with breast cancer risk. Hum Mol Genet 18(6):1131–1139

    Article  PubMed  CAS  Google Scholar 

  17. Li N, Dong J, Hu Z, Shen H, Dai M (2010) Potentially functional polymorphisms in ESR1 and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 121(1):177–184

    Article  PubMed  CAS  Google Scholar 

  18. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  PubMed  CAS  Google Scholar 

  19. Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19(4):251–253

    Article  PubMed  CAS  Google Scholar 

  20. Antoniou AC, Kartsonaki C, Sinilnikova OM, Soucy P, McGuffog L et al (2011) Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 20(16):3304–3321

    Article  PubMed  CAS  Google Scholar 

  21. Cai Q, Wen W, Qu S, Li G, Egan KM et al (2011) Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of Chinese, Japanese, and European ancestry. Cancer Res 71(4):1344–1355

    Article  PubMed  CAS  Google Scholar 

  22. Campa D, Kaaks R, Le Marchand L, Haiman CA, Travis RC et al (2011) Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 103(16):1252–1263

    Article  PubMed  Google Scholar 

  23. Chan M, Ji SM, Liaw CS, Yap YS, Law HY et al (2012) Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population. Breast Cancer Res Treat 136(1):209–220

    Article  PubMed  CAS  Google Scholar 

  24. Han W, Woo JH, Yu JH, Lee MJ, Moon HG et al (2011) Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype. Cancer Epidemiol Biomarkers Prev 20(5):793–798

    Article  PubMed  CAS  Google Scholar 

  25. Hein R, Maranian M, Hopper JL, Kapuscinski MK, Southey MC et al (2012) Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC). PLoS ONE 7(8):e42380

    Article  PubMed  CAS  Google Scholar 

  26. Jiang Y, Han J, Liu J, Zhang G, Wang L et al (2011) Risk of genome-wide association study newly identified genetic variants for breast cancer in Chinese women of Heilongjiang Province. Breast Cancer Res Treat 128(1):251–257

    Article  PubMed  Google Scholar 

  27. Kim HC, Lee JY, Sung H, Choi JY, Park SK et al (2012) A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study. Breast Cancer Res 14(2):R56

    Article  PubMed  CAS  Google Scholar 

  28. Mulligan AM, Couch FJ, Barrowdale D, Domchek SM, Eccles D et al (2011) Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2. Breast Cancer Res 13(6):R110

    Article  PubMed  CAS  Google Scholar 

  29. Ruiz-Narvaez EA, Rosenberg L, Yao S, Rotimi CN, Cupples AL et al (2012) Fine-mapping of the 6q25 locus identifies a novel SNP associated with breast cancer risk in African–American women. Carcinogenesis 34(2):287–291

    Article  PubMed  Google Scholar 

  30. Stacey SN, Sulem P, Zanon C, Gudjonsson SA, Thorleifsson G et al (2010) Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus. PLoS Genet 6(7):e1001029

    Article  PubMed  Google Scholar 

  31. Stevens KN, Vachon CM, Lee AM, Slager S, Lesnick T et al (2011) Common breast cancer susceptibility loci are associated with triple-negative breast cancer. Cancer Res 71(19):6240–6249

    Article  PubMed  CAS  Google Scholar 

  32. Sueta A, Ito H, Kawase T, Hirose K, Hosono S et al (2012) A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population. Breast Cancer Res Treat 132(2):711–721

    Article  PubMed  CAS  Google Scholar 

  33. Cancer CGoHFiB (2002) Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360(9328):187–195

    Article  Google Scholar 

  34. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108

    Article  PubMed  Google Scholar 

  35. Garcia-Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J et al (2008) Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 4(4):e1000054

    Article  PubMed  Google Scholar 

  36. Long J, Shu XO, Cai Q, Gao YT, Zheng Y et al (2010) Evaluation of breast cancer susceptibility loci in Chinese women. Cancer Epidemiol Biomarkers Prev 19(9):2357–2365

    Article  PubMed  CAS  Google Scholar 

  37. Key T, Appleby P, Barnes I, Reeves G (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94(8):606–616

    Article  PubMed  CAS  Google Scholar 

  38. Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA et al (2008) Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 82(4):937–948

    Article  PubMed  CAS  Google Scholar 

  39. Antoniou AC, Sinilnikova OM, McGuffog L, Healey S, Nevanlinna H et al (2009) Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 18(22):4442–4456

    Article  PubMed  CAS  Google Scholar 

  40. Antoniou AC, Beesley J, McGuffog L, Sinilnikova OM, Healey S et al (2010) Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 70(23):9742–9754

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of General Surgery, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China

    Ziang Yang

  2. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China

    Juping Shen & Zhigang Cao

  3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China

    Juping Shen, Zhigang Cao & Biyun Wang

  4. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China

    Biyun Wang

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  1. Ziang Yang
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  2. Juping Shen
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Correspondence to Biyun Wang.

Additional information

Ziang Yang and Juping Shen contributed equally to this study.

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Yang, Z., Shen, J., Cao, Z. et al. Association between a novel polymorphism (rs2046210) of the 6q25.1 locus and breast cancer risk. Breast Cancer Res Treat 139, 267–275 (2013). https://doi.org/10.1007/s10549-013-2494-1

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  • DOI: https://doi.org/10.1007/s10549-013-2494-1

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