Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Abstract

Background

Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.

Methods

Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.

Results

Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.

Conclusion

This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

Metadata

Item Type:	Article
Authors/Creators:	Ahearn, TU Zhang, H Michailidou, K Milne, RL Bolla, MK Dennis, J Dunning, AM Lush, M Wang, Q Andrulis, IL Anton-Culver, H Arndt, V Aronson, KJ Auer, PL Augustinsson, A Baten, A Becher, H Behrens, S Benitez, J Bermisheva, M Blomqvist, C Bojesen, SE Bonanni, B Børresen-Dale, A-L Brauch, H Brenner, H Brooks-Wilson, A Brüning, T Burwinkel, B Buys, SS Canzian, F Castelao, JE Chang-Claude, J Chanock, SJ Chenevix-Trench, G Clarke, CL Sahlberg, KK Ottestad, L Kåresen, R Schlichting, E Holmen, MM Sauer, T Haakensen, V Engebråten, O Naume, B Fosså, A Kiserud, CE Reinertsen, KV Helland, Å Riis, M Geisler, J Collée, JM Cox, A https://orcid.org/0000-0002-5138-1099 Cross, SS Czene, K Daly, MB Devilee, P Dörk, T Dwek, M Eccles, DM Evans, DG Fasching, PA Figueroa, J Floris, G Gago-Dominguez, M Gapstur, SM García-Sáenz, JA Gaudet, MM Giles, GG Goldberg, MS González-Neira, A Alnæs, GIG Grip, M Guénel, P Haiman, CA Hall, P Hamann, U Harkness, EF Heemskerk-Gerritsen, BAM Holleczek, B Hollestelle, A Hooning, MJ Hoover, RN Hopper, JL Howell, A Clarke, C Balleine, R Baxter, R Braye, S Carpenter, J Dahlstrom, J Forbes, J Lee, C Marsh, D Morey, A Pathmanathan, N Scott, R Simpson, P Spigelman, A Wilcken, N Yip, D Zeps, N Fox, S Campbell, I Bowtell, D Chenevix-Trench, G Spurdle, A Webb, P de Fazio, A Tassell, M Kirk, J Lindeman, G Price, M Southey, M Milne, R Deb, S Jakimovska, M Jakubowska, A John, EM Jones, ME Jung, A Kaaks, R Kauppila, S Keeman, R Khusnutdinova, E Kitahara, CM Ko, Y-D Koutros, S Kristensen, VN Krüger, U Kubelka-Sabit, K Kurian, AW Kyriacou, K Lambrechts, D Lee, DG Lindblom, A Linet, M Lissowska, J Llaneza, A Lo, W-Y MacInnis, RJ Mannermaa, A Manoochehri, M Margolin, S Martinez, ME McLean, C Meindl, A Menon, U Nevanlinna, H Newman, WG Nodora, J Offit, K Olsson, H Orr, N Park-Simon, T-W Patel, AV Peto, J Pita, G Plaseska-Karanfilska, D Prentice, R Punie, K Pylkäs, K Radice, P Rennert, G Romero, A Rüdiger, T Saloustros, E Sampson, S Sandler, DP Sawyer, EJ Schmutzler, RK Schoemaker, MJ Schöttker, B Sherman, ME Shu, X-O Smichkoska, S Southey, MC Spinelli, JJ Swerdlow, AJ Tamimi, RM Tapper, WJ Taylor, JA Teras, LR Terry, MB Torres, D Troester, MA Vachon, CM van Deurzen, CHM van Veen, EM Wagner, P Weinberg, CR Wendt, C Wesseling, J Winqvist, R Wolk, A Yang, XR Zheng, W Couch, FJ Simard, J Kraft, P Easton, DF Pharoah, PDP Schmidt, MK García-Closas, M Chatterjee, N
Copyright, Publisher and Additional Information:	© 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Keywords:	Breast cancer; Etiologic heterogeneity; Genetic predisposition; Common breast cancer susceptibility variants
Dates:	Published: 4 January 2022 Published (online): 4 January 2022 Accepted: 2 November 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	13 Jan 2022 07:30
Last Modified:	13 Jan 2022 07:30
Status:	Published
Publisher:	BioMed Central
Refereed:	Yes
Identification Number:	10.1186/s13058-021-01484-x
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:182324

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Common variants in breast cancer risk loci predispose to distinct tumor subtypes

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