Abstract
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10−35), 12q24 (rs1292011; P = 4.3 × 10−19) and 21q21 (rs2823093; P = 1.1 × 10−12). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
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Acknowledgements
We thank the following individuals for their contribution to this project (study names given in parentheses): S. Cornelissen, R. van Hien, L. Braaf, L. Van't Veer, B. Bueno-de-Mesquita and S. Canisius (ABCS); N. McInerney, G. Colleran, A. Rowan and N. Miller (BIGGS); A. Langheinz (BSUCH); J.I. Arias Pérez, P. Zamora, P. Menendez, T. Moreno and G. Pita (CNIO-BCS); M. Adank, M. Ausems and S. Verhoef (DFBBCS); U. Hamann, Y.-D. Ko, C. Baisch, H.-P. Fischer, B. Pesch, S. Rabstein and V. Harth (GENICA); K. Aaltonen, P. Heikkilä, T. Heikkinen, D. Greco, R.N.H. Jäntti and I. Erkkilä (HEBCS); H. Kemiläinen, E. Myöhänen and A. Parkkinen (KBCP); T. Slanger, E. Mutschelknauss, S. Behrens, R. Birr, M. Celik, U. Eilber, B. Kaspereit, N. Knese and K. Smit (MARIE); P. Radice, B. Peissel, M. Barile and M.A. Pierotti (MBCSG); T. Selander, M. Gill, L. Collins and N. Weerasooriya (OFBCR); M. Grip, K. Mononen and M. Otsukka (OBCS); E. Krol-Warmerdam and J. Blom (ORIGO); and P. Boonyawongviroj and P. Siriwanarungsan (ACP). For full acknowledgments, including funding sources, see the Supplementary Note.
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M.G. and D.F.E. wrote the manuscript. K.M., M.G. and D.F.E. performed the statistical analysis. O.F., N.J., N.O., I.d.S.S., M.L. and J.P. led the BBCS GWAS. D.F.E., P.D.P.P., A.M.D., C.T. and N.R. led the UK2 GWAS. Q. Waisfisz and H.M.-H. led the DFBBCS GWAS, with support from A.G.U. and F.R., P. Hall, K.C., A.I. and J. Liu led the SASBAC GWAS. H.N., K.A. and C. Blomqvist led the HEBCS GWAS. A. Meindl, R.K.S., B.M.-M. and P.L. led the GC-HBOC GWAS. J.C.-C., R.H., S.N. and D.F.-J. led the MARIE GWAS. J.L.H., M. Southey, H.T., E.M., D.S. and M. Bui led the ABCFS/kConFab GWAS. D.J.H. and S.J.C. led the CGEMS GWAS. E.D. and J.D. provided bioinformatics support. Q. Wang, M.K.H. and K.D. provided data management support for BCAC. C.L., C. Baynes, D.C., M.M. and S.A. managed centralized genotyping for BCAC samples. M.K.S. provided gene expression analysis. J.L.H., M. Southey, C.A. and D.J.P. coordinated the ABCFR study. M.K.S., A.B., S.V. and F.B.L.H. coordinated ABCS. P.A.F., M.P.L., M.W.B. and A.B.E. coordinated the BBCC study. E.S., I.T. and M.K. coordinated BIGGS. F. Marme, A. Schneeweiss, C. Sohn and B. Burwinkel coordinated the BSUCH study. P.G., T.T., E.C.-D. and F. Menegaux coordinated the CECILE study. S.E.B., B.G.N. and S.F.N. coordinated CGPS. R.L.M., M.R.A., A.G.-N. and J. Benítez coordinated CNIO-BCS. H.A.-C., A.Z., L. Bernstein and C.C.D. coordinated CTS. H. Brenner, H.M., V.A. and C. Stegmaier coordinated the ESTHER study. C.J., H. Brauch and T.B. coordinated the GENICA study. J.C.-C., S.W.-G. and U.E. coordinated the GESBC study. T.D., P.S., M. Bremer and P. Hillemanns coordinated HABCS. N.V.B., N.N.A., Y.I.R., J.H.K. and T.D. coordinated HMBCS. M. Bermisheva, D.P., N.V.B., T.D. and E.K. coordinated HUBCS. A. Lindblom and S. Margolin coordinated the KARBAC study. A. Mannermaa, V. Kataja, V.-M.K. and J.M.H. coordinated the KBCP study. D.L., B.T.Y., G.F. and K.L. coordinated the LMBC study. S. Manoukian, B. Bonanni, S.F. and P.P. coordinated the MBCSG study. F.J.C., X.W., K.S. and A. Lee coordinated the MCBCS study. M. Southey, G.G.G., L. Baglietto, G.S. and C.M. coordinated MCCS. G.G.A., V. Kristensen and A.-L.B.-D. coordinated NBCS. E.M.J. and A. Miron coordinated the NC-BCFR study. R.W., K.P., A.J.-V. and S.K. coordinated OBCS. I.L.A., G.G. and A.M.M. coordinated the OFBCR study. P.D. C.J.v.A., R.A.E.M.T. and C. Seynaeve coordinated the ORIGO study. J.D.F., M.G.-C., L. Brinton and J. Lissowska coordinated PBCS. M.J.H., A.H., R.A.O. and A.M.W.v.d.O. coordinated RBCS. A. Cox and M.W.R.R. coordinated SBCS. B.A.J.P. initiated SEARCH with P.D.P.P. and D.F.E., M. Shah coordinated SEARCH. A.J., J. Lubinski, K.J. and K. Durda coordinated SZBCS. M.J., M. Schoemaker, A.A. and A. Swerdlow coordinated UKBGS. G.C.-T. led the contribution of kConFab cases and AOCS controls to BCAC, and J. Beesley and X.C. performed iPLEX genotyping for several of the BCAC sites. K.R.M., A. Lophatananon, S.R. and A. Chaiwerawattana coordinated the ACP study. D.K., K.-Y.Y. and D.-Y.N. coordinated SEBCS. C.-Y.S. J.-C.Y., P.-E.W. and C.-N.H. coordinated TWBCS. A.P., R.S. and L.V. coordinated DBCSS. D.M.E., W.J.T., S.M.G. and N.J.G. coordinated the POSH study. HEBON organized the patient recruitment and data and sample collection for the DFBBCS GWAS. FBCS organized patient recruitment and data and sample collection for the UK2 GWAS. The GENICA Network organized patient recruitment and data and sample collection for the GENICA study. kConFab investigators and the Australian Ovarian Cancer Study organized recruitment and data and sample collection for kConFab and AOCS, respectively.
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A full list of contributing authors is provided in the Supplementary Note.
A full list of contributing authors is provided in the Supplementary Note.
A full list of contributing authors is provided in the Supplementary Note.
A full list of contributing authors is provided in the Supplementary Note.
A full list of contributing authors is provided in the Supplementary Note.
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Ghoussaini, M., Fletcher, O., Michailidou, K. et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 44, 312–318 (2012). https://doi.org/10.1038/ng.1049
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DOI: https://doi.org/10.1038/ng.1049
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