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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer


Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

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Figure 1: A regional plot of the −log10 P values for SNPs at the chromosome 5p15 risk locus from the meta-analysis of the AABC and TNBCC stage 1 studies.


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This work was supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to C.A.H. (W81XWH-08-1-0383), the Norris Foundation, the Mayo Clinic College of Medicine, Komen Foundation for the Cure, the Breast Cancer Research Foundation and US National Institutes of Health grants CA128978, CA122340 and CA148065. Study specific acknowledgments are listed in the Supplementary Note.

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Conceived of and designed the experiments: C.A.H. and F.J.C. Performed the experiments and analyzed the data: C.A.H., L.C.P., D.V.D.B., X.S., G.K.C., A. Holbrook, P.W., F.C., D.O.S., X.W., T.L., C.O., K.N.S., A.M.L., L.Y.X., S.L.S. and C.M.V. Contributed reagents, materials, analysis tools or comments on the manuscript: C.A.H., C.M.V., A.D., R.C.M., X.W., F.A., S.A., C.B.A., L. Baglietto, R.B., E.V.B., M.W.B., C.D.B., L. Bernstein, C.B., W.J.B., H.B., J.E.B., L.A.C., J.E.C., J.C.-C., S.J.C., D.I.C., C.L.C., A.C., S.S.C., S.L.D., R.B.D., A.M.D., W.R.D., T.D., L.D., D.E., C.K.E., A.B.E., P.A.F., H.S.F., D.F.-J., F.F., A.F., G.F., S.M.G., G.G.G., A.K.G., P.G., N.G., D.G., U.H., S.E.H., A. Hartmann, R.H., J.H., R.N.H., J.J.H., D.J.H., S.A.I., A.I., J.I., E.M.J., N.J., A.J.-V., R.K., Y.-D.K., L.N.K., I.K., V.-M.K., S.K., D.L., A.M.L., L.L.M., T.L., J.L., S.L., A.M., S.M., N.G.M., P.M., G.W.M., H.N., S. Nickels, S. Nyante, C.O., J. Palmer, H.P., D.P., C.M.P., J. Peto, P.D.P.P., L.C.P., M.F.P., K.P., T.R.R., J.L.R.-G., L.R., E.R., T.R., I.d.S.S., E.S., M.K.S., R.S.-W., F.S., G.S., X.S., L.B.S., H.-P.S., K.N.S., M.C.S., W.J.T., I.T., F.B.L.H., E.W., J.W., H.W., R.W., D.Y., W.Z., R.G.Z., A.S., S.L.S., D.O.S., D.E., P.K., B.E.H. and F.J.C. Wrote the paper: C.A.H. and F.J.C.

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Correspondence to Christopher A Haiman or Fergus J Couch.

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The authors declare no competing financial interests.

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A full list of members is provided in the Supplementary Note.

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Supplementary Tables 1–4, Supplementary Figures 1 and 2 and Supplementary Note (PDF 556 kb)

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Haiman, C., Chen, G., Vachon, C. et al. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer. Nat Genet 43, 1210–1214 (2011).

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