Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Carey, L.A. et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. J. Am. Med. Assoc. 295, 2492–2502 (2006).
Huo, D. et al. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J. Clin. Oncol. 27, 4515–4521 (2009).
Sørlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 98, 10869–10874 (2001).
Antoniou, A.C. et al. 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, 885–892 (2010).
Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).
Haiman, C.A. et al. A common genetic risk factor for colorectal and prostate cancer. Nat. Genet. 39, 954–956 (2007).
Kiemeney, L.A. et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).
Purdue, M.P. et al. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat. Genet. 43, 60–65 (2011).
Thomas, G. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).
Turnbull, C. et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat. Genet. 42, 504–507 (2010).
Baird, D.M. Variation at the TERT locus and predisposition for cancer. Expert Rev. Mol. Med. 12, e16 (2010).
Johnatty, S.E. et al. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility “hot-spot”. PLoS Genet. 6, e1001016 (2010).
McKay, J.D. et al. Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404–1406 (2008).
Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899–904 (2009).
Bolton, K.L. et al. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat. Genet. 42, 880–884 (2010).
Acknowledgements
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.
Author information
Authors and Affiliations
Consortia
Contributions
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.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Additional information
A full list of members is provided in the Supplementary Note.
Supplementary information
Supplementary Text and Figures
Supplementary Tables 1–4, Supplementary Figures 1 and 2 and Supplementary Note (PDF 556 kb)
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1038/ng.985
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.985
This article is cited by
-
Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction
Nature Genetics (2024)
-
The comparison of cancer gene mutation frequencies in Chinese and U.S. patient populations
Nature Communications (2022)
-
Quantitative assessment of the immune microenvironment in African American Triple Negative Breast Cancer: a case–control study
Breast Cancer Research (2021)
-
Precise diagnosis of three top cancers using dbGaP data
Scientific Reports (2021)
-
Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women
Nature Communications (2021)
