Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses
Authors
Zhang, H.Ahearn, T. U.
Lecarpentier, J.
Barnes, D.
Beesley, J.
Qi, G.
Jiang, X.
O'Mara, T. A.
Zhao, N.
Bolla, M. K.
Dunning, A. M.
Dennis, J.
Wang, Q.
Ful, Z. A.
Aittomaki, K.
Andrulis, I. L.
Anton-Culver, H.
Arndt, V.
Aronson, K. J.
Arun, B. K.
Auer, P. L.
Azzollini, J.
Barrowdale, D.
Becher, H.
Beckmann, M. W.
Behrens, S.
Benitez, J.
Bermisheva, M.
Bialkowska, K.
Blanco, A.
Blomqvist, C.
Bogdanova, N. V.
Bojesen, S. E.
Bonanni, B.
Bondavalli, D.
Borg, A.
Brauch, H.
Brenner, H.
Briceno, I.
Broeks, A.
Brucker, S. Y.
Bruning, T.
Burwinkel, B.
Buys, S. S.
Byers, H.
Caldes, T.
Caligo, M. A.
Calvello, M.
Campa, D.
Castelao, J. E.
Chang-Claude, J.
Chanock, S. J.
Christiaens, M.
Christiansen, H.
Chung, W. K.
Claes, K. B. M.
Clarke, C. L.
Cornelissen, S.
Couch, F. J.
Cox, A.
Cross, S. S.
Czene, K.
Daly, M. B.
Devilee, P.
Diez, O.
Domchek, S. M.
Dork, T.
Dwek, M.
Eccles, D. M.
Ekici, A. B.
Evans, D. G.
Fasching, P. A.
Figueroa, J.
Foretova, L.
Fostira, F.
Friedman, E.
Frost, D.
Gago-Dominguez, M.
Gapstur, S. M.
Garber, J.
Garcia-Saenz, J. A.
Gaudet, M. M.
Gayther, S. A.
Giles, G. G.
Godwin, A. K.
Goldberg, M. S.
Goldgar, D. E.
Gonzalez-Neira, A.
Greene, M. H.
Gronwald, J.
Guenel, P.
Haberle, L.
Hahnen, E.
Haiman, C. A.
Hake, C. R.
Hall, P.
Hamann, U.
Harkness, E. F.
Heemskerk-Gerritsen, B. A. M.
Hillemanns, P.
Hogervorst, F. B. L.
Holleczek, B.
Hollestelle, A.
Hooning, M. J.
Hoover, R. N.
Hopper, J. L.
Howell, Anthony
Huebner, H.
Hulick, P. J.
Imyanitov, E. N.
Isaacs, C.
Izatt, L.
Jager, A.
Jakimovska, M.
Jakubowska, A.
James, P.
Janavicius, R.
Janni, W.
John, E. M.
Jones, M. E.
Jung, A.
Kaaks, R.
Kapoor, P. M.
Karlan, B. Y.
Keeman, R.
Khan, S.
Khusnutdinova, E.
Kitahara, C. M.
Ko, Y. D.
Konstantopoulou, I.
Koppert, L. B.
Koutros, S.
Kristensen, V. N.
Laenkholm, A. V.
Lambrechts, D.
Larsson, S. C.
Laurent-Puig, P.
Lazaro, C.
Lazarova, E.
Lejbkowicz, F.
Leslie, G.
Lesueur, F.
Lindblom, A.
Lissowska, J.
Lo, W. Y.
Loud, J. T.
Lubinski, J.
Lukomska, A.
MacInnis, R. J.
Mannermaa, A.
Manoochehri, M.
Manoukian, S.
Margolin, S.
Martinez, M. E.
Matricardi, L.
McGuffog, L.
McLean, C.
Mebirouk, N.
Meindl, A.
Menon, U.
Miller, A.
Mingazheva, E.
Montagna, M.
Mulligan, A. M.
Mulot, C.
Muranen, T. A.
Nathanson, K. L.
Neuhausen, S. L.
Nevanlinna, H.
Neven, P.
Newman, W. G.
Nielsen, F. C.
Nikitina-Zake, L.
Nodora, J.
Offit, K.
Olah, E.
Olopade, O. I.
Olsson, H.
Orr, N.
Papi, L.
Papp, J.
Park-Simon, TW
Parsons, M. T.
Peissel, B.
Peixoto, A.
Peshkin, B.
Peterlongo, P.
Peto, J.
Phillips, K. A.
Piedmonte, M.
Plaseska-Karanfilska, D.
Prajzendanc, K.
Prentice, R.
Prokofyeva, D.
Rack, B.
Radice, P.
Ramus, S. J.
Rantala, J.
Rashid, M. U.
Rennert, G.
Rennert, H. S.
Risch, H. A.
Romero, A.
Rookus, M. A.
Rubner, M.
Rudiger, T.
Saloustros, E.
Sampson, S.
Sandler, D. P.
Sawyer, E. J.
Scheuner, M. T.
Schmutzler, R. K.
Schneeweiss, A.
Schoemaker, M. J.
Schottker, B.
Schurmann, P.
Senter, L.
Sharma, P.
Sherman, M. E.
Shu, X. O.
Singer, C. F.
Smichkoska, S.
Soucy, P.
Southey, M. C.
Spinelli, J. J.
Stone, J.
Stoppa-Lyonnet, D.
Study, E.
Collaborators, G. S.
Swerdlow, A. J.
Szabo, C. I.
Tamimi, R. M.
Tapper, W. J.
Taylor, J. A.
Teixeira, M. R.
Terry, M.
Thomassen, M.
Thull, D. L.
Tischkowitz, M.
Toland, A. E.
Tollenaar, R.
Tomlinson, I.
Torres, D.
Troester, M. A.
Truong, T.
Tung, N.
Untch, M.
Vachon, C. M.
van den Ouweland, A. M. W.
van der Kolk, L. E.
van Veen, E. M.
vanRensburg, E. J.
Vega, A.
Wappenschmidt, B.
Weinberg, C. R.
Weitzel, J. N.
Wildiers, H.
Winqvist, R.
Wolk, A.
Yang, X. R.
Yannoukakos, D.
Zheng, W.
Zorn, K. K.
Milne, R. L.
Kraft, P.
Simard, J.
Pharoah, P. D. P.
Michailidou, K.
Antoniou, A. C.
Schmidt, M. K.
Chenevix-Trench, G.
Easton, D. F.
Chatterjee, N.
Garcia-Closas, M.
Affiliation
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.Issue Date
2020
Metadata
Show full item recordAbstract
Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.Citation
H. Zhang, T. U. Ahearn, J. Lecarpentier et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet. 2020;52(6):572-581.Journal
Nature GeneticsDOI
10.1038/s41588-020-0609-2PubMed ID
32424353Additional Links
https://dx.doi.org/10.1038/s41588-020-0609-2Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1038/s41588-020-0609-2
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