Rare germline copy number variants (CNVs) and breast cancer risk.

Abstract

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Metadata

Item Type:	Article
Authors/Creators:	Dennis, J Tyrer, JP Walker, LC Michailidou, K Dorling, L Bolla, MK Wang, Q Ahearn, TU Andrulis, IL Anton-Culver, H Antonenkova, NN Arndt, V Aronson, KJ Freeman, LEB Beckmann, MW Behrens, S Benitez, J Bermisheva, M Bogdanova, NV Bojesen, SE Brenner, H Castelao, JE Chang-Claude, J Chenevix-Trench, G Clarke, CL NBCS Collaborators Collée, JM CTS Consortium Couch, FJ Cox, A https://orcid.org/0000-0002-5138-1099 Cross, SS Czene, K Devilee, P Dörk, T Dossus, L Eliassen, AH Eriksson, M Evans, DG Fasching, PA Figueroa, J Fletcher, O Flyger, H Fritschi, L Gabrielson, M Gago-Dominguez, M García-Closas, M Giles, GG González-Neira, A Guénel, P Hahnen, E Haiman, CA Hall, P Hollestelle, A Hoppe, R Hopper, JL Howell, A ABCTB Investigators kConFab/AOCS Investigators Jager, A Jakubowska, A John, EM Johnson, N Jones, ME Jung, A Kaaks, R Keeman, R Khusnutdinova, E Kitahara, CM Ko, Y-D Kosma, V-M Koutros, S Kraft, P Kristensen, VN Kubelka-Sabit, K Kurian, AW Lacey, JV Lambrechts, D Larson, NL Linet, M Ogrodniczak, A Mannermaa, A Manoukian, S Margolin, S Mavroudis, D Milne, RL Muranen, TA Murphy, RA Nevanlinna, H Olson, JE Olsson, H Park-Simon, T-W Perou, CM Peterlongo, P Plaseska-Karanfilska, D Pylkäs, K Rennert, G Saloustros, E Sandler, DP Sawyer, EJ Schmidt, MK Schmutzler, RK Shibli, R Smeets, A Soucy, P Southey, MC Swerdlow, AJ Tamimi, RM Taylor, JA Teras, LR Terry, MB Tomlinson, I Troester, MA Truong, T Vachon, CM Wendt, C Winqvist, R Wolk, A Yang, XR Zheng, W Ziogas, A Simard, J Dunning, AM Pharoah, PDP Easton, DF
Copyright, Publisher and Additional Information:	© The Author(s) 2022. Open Access: 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 18 January 2022 Published (online): 18 January 2022 Accepted: 1 December 2021
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 TB2017SHEF BREAST CANCER NOW TB2018SHEF BREAST CANCER NOW TB2O19BAR
Depositing User:	Symplectic Sheffield
Date Deposited:	27 Jan 2022 09:37
Last Modified:	27 Jan 2022 09:37
Status:	Published
Publisher:	Nature Research (part of Springer Nature)
Refereed:	Yes
Identification Number:	10.1038/s42003-021-02990-6
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:182979

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Rare germline copy number variants (CNVs) and breast cancer risk.

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