Abstract
Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
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Acknowledgements
The authors wish to thank all the individuals who took part in these studies and all the researchers, clinicians and administrative staff who have enabled this work to be carried out. We are very grateful to Illumina, in particular J. Stone, S. McBean, J. Hadlington, A. Mustafa and K. Cook, for their help with designing the array. BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of BCAC have been funded by the European Union European Cooperation in Science and Technology (COST) programme (BM0606). BPC3 is funded by US National Cancer Institute cooperative agreements U01-CA98233, U01-CA98710, U01-CA98216 and U01-CA98758 and the Intramural Research Program of the US National Institutes of Health (NIH)/National Cancer Institute, Division of Cancer Epidemiology and Genetics. TNBCC is supported by Mayo Clinic Breast Cancer Study (MCBCS) (US NIH grants CA122340 and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201)), grants from the Komen Foundation for the Cure and the Breast Cancer Research Foundation. Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), US NIH grant CA122340, the Komen Foundation for the Cure, the Breast Cancer Research Foundation, the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program (J. Simiard and D.E.) and Ministry of Economic Development, Innovation and Export Trade of Quebec grant PSR-SIIRI-701 (J. Simiard, D.E. and P.H.). J. Simiard holds the Canada Research Chair in Oncogenetics. Combination of the GWAS data was supported in part by US NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065-01 (DRIVE, part of the GAME-ON initiative) and Breakthrough Breast Cancer Research.
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M.G.-C., F.J.C., S.L., K. Michailidou, M.K.S., P.D.P.P., C.V., D.F.E., C.A.H. and P. Kraft formed the writing group and drafted the manuscript. M.G.-C. coordinated the writing group. F.J.C., S.L., K. Michaildou, D.F.E., C.A.H. and P. Kraft performed statistical analyses of GWAS data. M.G.-C. and M.N.B. performed statistical analyses of BCAC follow-up studies and meta-analyses. P. Kraft coordinated the BPC3 GWAS, and M.G.-C., E.R., H.S.F., L.L.M., J.E.B., W.C.W., D.J.H. and S.J.C. led individual studies in the BPC3 scan. F.J.C. and C.V. coordinated the TNBCC GWAS, and D.E., P. Miron, P.A.F., J.C.-C., J.C., A.A., H.N., H. Brauch and G.G.G. led individual studies in the TNBCC scan. D.E. coordinated the C-BCAC GWAS, and H.N., J.L.H., J.C.-C. and P.H. led individual studies in the C-BCAC scan. D.F.E. conceived and coordinated the synthesis of the iCOGS array and led BCAC. P.H. coordinated COGS, and J.B. led the BCAC genotyping working group. A.G.-N., G.P., M.R.A., D.V., F.B., D.C.T. and F.J.C. coordinated genotyping of the iCOGS array. M.G.-C., P.D.P.P. and M.K.S. led the pathology working group in BCAC. M.E.S. was the lead pathologist in BCAC. W.J.H. performed automated scoring of tissue microarrays. A.M.D. and G.C.-T. led the quality control working group. J.D. and N.O. provided bioinformatics support. S.K.R. and G.A.C. performed FunciSNP bioinformatics analyses. M.K.B. and Q. Wang provided data management support for BCAC. G.G., A.A., A. Broeks, A.B.E., A.C., U.H., A.-S.D., A.G.U., A.H., A.H.W., A.I., the ABCTB Investigators, A.J.-V., A.J., A.K.G., R.W., A. Lindblom, A. Lophatananon, A.M.D., A.M.M., A.M.W.v.d.O., A.R., A. Swerdlow, A. Schneeweiss, B.B., B.E.H., B.G.N., B.M.-M., B.P., C.B., C.B.A., C.-Y.C., C.C., C.D.B., C.-N.H., C.H.M.v.D., C.H.Y., C.J., C.M., C.M.S., C.O., C.R., C.-Y.S., C. Sohn, C. Stegmaier, C.-C.T., C.T., C.W.C., D.C., D.C.T., D.F.-J., D.G., D.I.C., D.J.P., D.J.S., D.K., D.L., D.O.S., D.S., D.T., D.V.D.B., E.D., C.V., E.J.R., E.J.S., E.M., E.M.J., E.V.B., E.W., F.A., FBCS, F.C.-C., F.C., F.H., F.L., F.M., F.R., F.S., G.A.C., G.C.-T., G.K.C., G.S., G.W.M., H.A.-C., H.C., H.F., H. Ito, H. Iwata, H. Müller, H. Miao, H.M.-H., H.P., H.T., H.W., I.d.S.S., I.K., I.L.A., I.T., J.A.K., J.D.F., J.E.O., J.I.A.P., J.J.H., J. Long, J. Lubinski, J. Liu, J. Lissowska, J.L.R.-G., J.M.H., J.P., J. Stone, J. Simard, J.W., J.-C.Y., K. Aittomäki, K. Aaltonen, K.C., K.D., K.J., K.-T.K., K.L., K. Muir, K. Matsuo, K.P., K.S., K.S.C., L. Bernard, L. Baglietto, L. Bernstein, L. Beckmann, L.D., L.G., L.J.V.V., L.N.K., L.S., M.B., M.C.S., M.D., M.F.P., M.G.S., M. Jones, M. Johansson, M.J.H., M.J.K., M.K., M.K.B., M.L., M.M.G., M.P.L., M. Shrubsole, M. Shah, M.W.B., M.W.R.R., N.A.M.T., N.D., N.G.M., N.J., N.M., N.N.A., N.R., N.S., N.V.B., O.F., P.G., P.H., P.H.P., P. Kerbrat, P.L.-P., P.L., P. Menénde, P.N., P.P., P.R., P. Siriwanarangsan, P. Sharma, P.-E.W., Q.C., Q. Wang, Q. Waisfisz, R.B., R.G.Z., R.H., R.K., R.K.S., R.L.M., R.M.M., R.N.H., R.P., R.A.E.M.T., R. Tumino, R. Travis, S.A.I., S.E.B., S.E.H., S.F.N., S.G., S.H.T., S.K., S.K.R., S.L.D.-H., S.M., S.M.J., S. Nickels, S. Nyante, S.P.B., S. Sangrajrang, S.S.-B., S. Slager, S.S.C., T.A.M., T.B., T.D., T.H., T.T., V.A., V. Kristensen, V. Kataja, V.-M.K., W.B., W.L., W.R.D., W.T., X.-O.S., X.W., Y.F., Y.-T.G., Y.-D.K. and Y.Y. contributed to GWAS and/or BCAC follow-up studies. M.G.-C., F.J.C., S.L., K. Michailidou, M.K.S., P.D.P.P., C.V., D.F.E., C.A.H., P. Kraft, M.N.B., E.R., H.S.F., L.L.M., J.E.B., W.C.W., D.J.H., S.J.C., D.E., P.A.F., J.C.-C., J.C., A. Broeks, H.N., H. Brauch, H. Brenner, G.P., G.G.G., J.L.H., P. Miron, J.B., A.G.-N., M.R.A., D.V., F.B., M.E.S., W.J.H., G.G., A.A., A. Beck, A.B.E., A.C., U.H., A.-S.D., A.G.U., A.H., A.H.W., A.I., the ABCTB Investigators, A.J.-V., A.J., A.K.G., R.W., A. Lindblom, A. Lophatananon, A.M.D., A.M.M., A.M.W.v.d.O., A.R., A. Swerdlow, A. Schneeweiss, B.B., B.E.H., B.G.N., B.M.-M., B.P., C.B., C.B.A., C.-Y.C., C.C., C.D.B., C.-N.H., C.H.M.v.D., C.H.Y., C.J., C.M., C.M.S., C.O., C.R., C.-Y.S., C. Sohn, C. Stegmaier, C.-C.T., C.T., C.W.C., D.C., D.C.T., D.F.-J., D.G., D.I.C., D.J.P., D.J.S., D.K., D.L., D.O.S., D.S., D.T., D.V.D.B., E.D., C.V., E.J.R., E.J.S., E.M., E.M.J., E.V.B., E.W., F.A., FBCS, F.C.-C., F.C., F.H., F.L., F.M., F.R., F.S., G.A.C., G.C.-T., G.K.C., G.S., G.W.M., H.A.-C., H.C., H.F., H. Ito, H. Iwata, H. Müller, H. Miao, H.M.-H., H.P., H.T., H.W., I.d.S.S., I.K., I.L.A., I.T., J.A.K., J.D., J.D.F., J.E.O., J.I.A.P., J.J.H., J. Long, J. Lubinski, J. Liu, J. Lissowska, J.L.R.-G., J.M.H., J.P., J. Stone, J. Simard, J.W., J.-C.Y., K. Aittomäki, K. Aaltonen, K.C., K.D., K.J., K.-T.K., K.L., K. Muir, K. Matsuo, K.P., K.S., K.S.C., L. Bernard, L. Baglietto, L. Bernstein, L. Beckmann, L.D., L.G., L.J.V.V., L.N.K., L.S., M.B., M.C.S., M.D., M.F.P., M.G.S., M.H., M. Jones, M. Johansson, M.J.H., M.J.K., M.K., M.K.B., M.L., M.M.G., M.P.L., M. Shrubsole, M. Shah, M.W.B., M.W.R.R., N.A.M.T., N.D., N.G.M., N.J., N.M., N.N.A., N.O., N.R., N.S., N.V.B., O.F., P.G., P.H., P.H.P., P. Kerbrat, P.L.-P., P.L., P. Menénde, P.N., P.P., P.R., P. Siriwanarangsan, P. Sharma, P.-E.W., Q.C., Q. Wang, Q. Waisfisz, R.B., R.G.Z., R.H., R.K., R.K.S., R.L.M., R.M.M., R.N.H., R.P., R.A.E.M.T., R. Tumino, R. Travis, S.A.I., S.E.B., S.E.H., S.F.N., S.G., S.H.T., S.K., S.K.R., S.L.D.-H., S.M., S.M.J., S. Nickels, S. Nyante, S.P.B., S. Sangrajrang, S.S.-B., S. Slager, S.S.C., T.A.M., T.B., T.D., T.H., T.T., V.A., V. Kristensen, V. Kataja, V.-M.K., W.B., W.L., W.R.D., W.T., X.-O.S., X.W., Y.F., Y.-T.G., Y.-D.K. A. Mannermaa, A. Meindl, W.Z., P.D., M.S.G. and Y.Y. provided critical review of the manuscript.
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Garcia-Closas, M., Couch, F., Lindstrom, S. et al. Genome-wide association studies identify four ER negative–specific breast cancer risk loci. Nat Genet 45, 392–398 (2013). https://doi.org/10.1038/ng.2561
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DOI: https://doi.org/10.1038/ng.2561
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