Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1,2,3. 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 × 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.

Metadata

Item Type:	Article
Authors/Creators:	Zhang, H Ahearn, TU Lecarpentier, J Barnes, D Beesley, J Qi, G Jiang, X O’Mara, TA Zhao, N Bolla, MK Dunning, AM Dennis, J Wang, Q Ful, ZA Aittomäki, K Andrulis, IL Anton-Culver, H Arndt, V Aronson, KJ Arun, BK Auer, PL Azzollini, J Barrowdale, D Becher, H Beckmann, MW Behrens, S Benitez, J Bermisheva, M Bialkowska, K Blanco, A Blomqvist, C Bogdanova, NV Bojesen, SE Bonanni, B Bondavalli, D Borg, A Brauch, H Brenner, H Briceno, I Broeks, A Brucker, SY Brüning, T Burwinkel, B Buys, SS Byers, H Caldés, T Caligo, MA Calvello, M Campa, D Castelao, JE Chang-Claude, J Chanock, SJ Christiaens, M Christiansen, H Chung, WK Claes, KBM Clarke, CL Cornelissen, S Couch, FJ Cox, A https://orcid.org/0000-0002-5138-1099 Cross, SS Czene, K Daly, MB Devilee, P Diez, O Domchek, SM Dörk, T Dwek, M Eccles, DM Ekici, AB Evans, DG Fasching, PA Figueroa, J Foretova, L Fostira, F Friedman, E Frost, D Gago-Dominguez, M Gapstur, SM Garber, J García-Sáenz, JA Gaudet, MM Gayther, SA Giles, GG Godwin, AK Goldberg, MS Goldgar, DE González-Neira, A Greene, MH Gronwald, J Guénel, P Häberle, L Hahnen, E Haiman, CA Hake, CR Hall, P Hamann, U Harkness, EF Heemskerk-Gerritsen, BAM Hillemanns, P Hogervorst, FBL Holleczek, B Hollestelle, A Hooning, MJ Hoover, RN Hopper, JL Howell, A Huebner, H Hulick, PJ Imyanitov, EN Isaacs, C Izatt, L Jager, A Jakimovska, M Jakubowska, A James, P Janavicius, R Janni, W John, EM Jones, ME Jung, A Kaaks, R Kapoor, PM Karlan, BY Keeman, R Khan, S Khusnutdinova, E Kitahara, CM Ko, Y-D Konstantopoulou, I Koppert, LB Koutros, S Kristensen, VN Laenkholm, A-V Lambrechts, D Larsson, SC Laurent-Puig, P Lazaro, C Lazarova, E Lejbkowicz, F Leslie, G Lesueur, F Lindblom, A Lissowska, J Lo, W-Y Loud, JT Lubinski, J Lukomska, A MacInnis, RJ Mannermaa, A Manoochehri, M Manoukian, S Margolin, S Martinez, ME Matricardi, L McGuffog, L McLean, C Mebirouk, N Meindl, A Menon, U Miller, A Mingazheva, E Montagna, M Mulligan, AM Mulot, C Muranen, TA Nathanson, KL Neuhausen, SL Nevanlinna, H Neven, P Newman, WG Nielsen, FC Nikitina-Zake, L Nodora, J Offit, K Olah, E Olopade, OI Olsson, H Orr, N Papi, L Papp, J Park-Simon, T-W Parsons, MT 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, SJ Rantala, J Rashid, MU Rennert, G Rennert, HS Risch, HA Romero, A Rookus, MA Rübner, M Rüdiger, T Saloustros, E Sampson, S Sandler, DP Sawyer, EJ Scheuner, MT Schmutzler, RK Schneeweiss, A Schoemaker, MJ Schöttker, B Schürmann, P Senter, L Sharma, P Sherman, ME Shu, X-O Singer, CF Smichkoska, S Soucy, P Southey, MC Spinelli, JJ Stone, J Stoppa-Lyonnet, D Swerdlow, AJ Szabo, CI Tamimi, RM Tapper, WJ Taylor, JA Teixeira, MR Terry, M Thomassen, M Thull, DL Tischkowitz, M Toland, AE Tollenaar, RAEM Tomlinson, I Torres, D Troester, MA Truong, T Tung, N Untch, M Vachon, CM van den Ouweland, AMW van der Kolk, LE van Veen, EM vanRensburg, EJ Vega, A Wappenschmidt, B Weinberg, CR Weitzel, JN Wildiers, H Winqvist, R Wolk, A Yang, XR Yannoukakos, D Zheng, W Zorn, KK Milne, RL Kraft, P Simard, J Pharoah, PDP Michailidou, K Antoniou, AC Schmidt, MK Chenevix-Trench, G Easton, DF Chatterjee, N García-Closas, M
Copyright, Publisher and Additional Information:	© 2020 The Author(s). This is an author-produced version of a paper subsequently published in Nature Genetics. Uploaded in accordance with the publisher's self-archiving policy.
Dates:	Published: June 2020 Published (online): 18 May 2020 Accepted: 5 March 2020
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield)
Funding Information:	Funder Grant number CANCER RESEARCH UK C9267/A25152 BREAST CANCER NOW TB2O19BAR
Depositing User:	Symplectic Sheffield
Date Deposited:	20 May 2020 14:47
Last Modified:	18 Nov 2021 14:12
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41588-020-0609-2
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:161038

CORE (COnnecting REpositories)

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Abstract

Metadata

Download

Accepted Version

Export

Statistics