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Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1

Abstract

We carried out a genome-wide association study among Chinese women to identify risk variants for breast cancer. After analyzing 607,728 SNPs in 1,505 cases and 1,522 controls, we selected 29 SNPs for a fast-track replication in an independent set of 1,554 cases and 1,576 controls. We further investigated four replicated loci in a third set of samples comprising 3,472 cases and 900 controls. SNP rs2046210 at 6q25.1, located upstream of the gene encoding estrogen receptor α (ESR1), showed strong and consistent association with breast cancer across all three stages. Adjusted odds ratio (95% CI) were 1.36 (1.24–1.49) and 1.59 (1.40–1.82), respectively, for genotypes A/G and A/A versus G/G (P for trend 2.0 × 10−15) in the pooled analysis of samples from all three stages. We also found a similar, albeit weaker, association in an independent study comprising 1,591 cases and 1,466 controls of European ancestry (Ptrend = 0.01). These results strongly implicate 6q25.1 as a susceptibility locus for breast cancer.

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Figure 1: Genome-wide association results in the Shanghai Breast Cancer Study.
Figure 2: Regional plot of the chromosome 6q25.1 locus.

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References

  1. Nathanson, K.L., Wooster, R. & Weber, B.L. Breast cancer genetics: what we know and what we need. Nat. Med. 7, 552–556 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Houlston, R.S. & Peto, J. The search for low-penetrance cancer susceptibility alleles. Oncogene 23, 6471–6476 (2004).

    Article  CAS  Google Scholar 

  4. Walsh, T. et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2 and TP53 in families at high risk of breast cancer. J. Am. Med. Assoc. 295, 1379–1388 (2006).

    Article  CAS  Google Scholar 

  5. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    Article  CAS  Google Scholar 

  6. Wooster, R. et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265, 2088–2090 (1994).

    Article  CAS  Google Scholar 

  7. Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat. Genet. 33(Suppl), 228–237 (2003).

    Article  CAS  Google Scholar 

  8. Pharoah, P.D., Tyrer, J., Dunning, A.M., Easton, D.F. & Ponder, B.A. Association between common variation in 120 candidate genes and breast cancer risk. PLoS Genet. 3, e42 (2007).

    Article  Google Scholar 

  9. Pharoah, P.D., Dunning, A.M., Ponder, B.A. & Easton, D.F. Association studies for finding cancer-susceptibility genetic variants. Nat. Rev. Cancer 4, 850–860 (2004).

    Article  CAS  Google Scholar 

  10. Cox, A. et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat. Genet. 39, 352–358 (2007).

    Article  CAS  Google Scholar 

  11. Frank, B. et al. Association of a common AKAP9 variant with breast cancer risk: a collaborative analysis. J. Natl. Cancer Inst. 100, 437–442 (2008).

    Article  CAS  Google Scholar 

  12. Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

    Article  CAS  Google Scholar 

  13. Hunter, D.J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870–874 (2007).

    Article  CAS  Google Scholar 

  14. Stacey, S.N. et al. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat. Genet. 40, 703–706 (2008).

    Article  CAS  Google Scholar 

  15. Gold, B. et al. Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc. Natl. Acad. Sci. USA 105, 4340–4345 (2008).

    Article  CAS  Google Scholar 

  16. Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Mitrunen, K. & Hirvonen, A. Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutat. Res. 544, 9–41 (2003).

    Article  CAS  Google Scholar 

  19. Cai, Q. et al. Association of breast cancer risk with a GT dinucleotide repeat polymorphism upstream of the estrogen receptor-α gene. Cancer Res. 63, 5727–5730 (2003).

    CAS  PubMed  Google Scholar 

  20. Cai, Q. et al. Genetic polymorphisms in the estrogen receptor α gene and risk of breast cancer: results from the Shanghai Breast Cancer Study. Cancer Epidemiol. Biomarkers Prev. 12, 853–859 (2003).

    CAS  PubMed  Google Scholar 

  21. Zheng, S.L. et al. Joint effect of estrogen receptor β sequence variants and endogenous estrogen exposure on breast cancer risk in Chinese women. Cancer Res. 63, 7624–7629 (2003).

    CAS  PubMed  Google Scholar 

  22. Kos, M., Reid, G., Denger, S. & Gannon, F. Minireview: genomic organization of the human ERα gene promoter region. Mol. Endocrinol. 15, 2057–2063 (2001).

    CAS  PubMed  Google Scholar 

  23. Styrkarsdottir, U. et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med. 358, 2355–2365 (2008).

    Article  CAS  Google Scholar 

  24. Hirano, T. At the heart of the chromosome: SMC proteins in action. Nat. Rev. Mol. Cell Biol. 7, 311–322 (2006).

    Article  CAS  Google Scholar 

  25. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  26. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  27. Lin, D.Y., Zeng, D. & Millikan, R. Maximum likelihood estimation of haplotype effects and haplotype-environment interactions in association studies. Genet. Epidemiol. 29, 299–312 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported in part by US National Institutes of Health grants R01CA124558, R01CA64277, R01CA70867, R01CA90899 and R01CA100374, as well as Ingram professorship funds and research award funds to W.Z., R01 CA118229, R01CA92585 and Department of Defense (DOD) Idea Award BC011118 to X.-O.S., and R01CA122756 and DOD Idea Award BC050791 to Q.C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors wish to thank study participants and research staff for their contributions and commitment to this project, R. Courtney and Q. Wang for DNA preparation, and B. Venuti for clerical support in the preparation of this manuscript. Sample preparation and stage 1 genotyping were conducted at the Survey and Biospecimen and Microarray Shared Resources that are supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). Stage 2 and 3 genotyping was carried out at the Proactive Genomics.

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Contributions

W.Z. directed the study and drafted the manuscript along with J.L., Q.C. and X.-O.S. J.L. coordinated the study and managed the genotyping data. Q.C. directed the lab operation. J.L., C.L. and W.W. performed statistical analyses. W.Z. directed the SBCS and the NBHS, and X.-O.S. directed the SBCSS and the SECS, the four parent studies. Y.-T.G., Y.-B.X. and W.L. directed the data and sample collection of SBCS, SBCSS and SECS in Shanghai. Y.Z. and K.G. supervised data and sample collection. S.L.D. and A.M.F. coordinated the NBHS. S.L. directed stage 1 genotyping. C.L., S.L. and J.L.H. contributed to manuscript revision. All authors reviewed and approved the final manuscript.

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Correspondence to Wei Zheng.

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Supplementary Methods, Supplementary Tables 1–4 and Supplementary Figures 1–3 (PDF 726 kb)

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Zheng, W., Long, J., Gao, YT. et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41, 324–328 (2009). https://doi.org/10.1038/ng.318

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