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

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 M, Behrens S, Benitez J, Bermisheva M, Bogdanova N, Bojesen SE, Brenner H, Castelao JE, Chang-Claude J, Chenevix-Trench G, Clarke CL, Collee JM, Couch FJ, Cox A, Cross SS, Czene K, Devilee P, Dork T, Dossus L, Eliassen AH, Eriksson M, Evans DG, Fasching P, Figueroa J, Fletcher O, Flyger H, Fritschi L, Gabrielson M, Gago-Dominguez M, Garcia-Closas M, Giles GG, Gonzalez-Neira A, Guenel P, Hahnen E, Haiman CA, Hall P, Hollestelle A, Hoppe R, Hopper JL, Howell A, Jager A, Jakubowska A, John EM, Johnson N, Jones ME, Jung A, Kaaks R, Keeman R, Khusnutdinova E, Kitahara CM, Ko YD, Kosma VM, Koutros S, Kraft P, Kristensen VN, Kubelka-Sabit K, Kurian AW, Lacey J, 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 TW, Perou CM, Peterlongo P, Plaseska-Karanfilska D, Pylkas 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 (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 5

Pages Range: 65-

Journal Issue: 1

DOI: 10.1038/s42003-021-02990-6

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.

Authors with CRIS profile

Involved external institutions

Karolinska Institute Sweden (SE) Ciber de Enfermedades Raras (CIBERER) Spain (ES) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Cambridge United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) National Cancer Institute (NCI) United States (USA) (US) University of Sheffield United Kingdom (GB) The Institute of Cancer Research (ICR) United Kingdom (GB) Erasmus University Medical Center (MC) Netherlands (NL) University of Southern California (USC) United States (USA) (US) Universität zu Köln Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Copenhagen University Hospital Denmark (DK) Queen's University United Kingdom (GB) Vanderbilt University United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Cancer Council Victoria Australia (AU) University of Sydney (USYD) Australia (AU) The University of Melbourne Australia (AU) École Polytechnique - Université Paris-Saclay France (FR) University of Edinburgh United Kingdom (GB) University of North Carolina at Chapel Hill United States (USA) (US) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) Russian Federation (RU) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Mayo Clinic United States (USA) (US) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology Belarus (BY) World Health Organization Switzerland (CH) Curtin University Australia (AU) Instituto de Investigación Sanitaria Galicia Sur Spain (ES) Mount Sinai Hospital (MSH) Canada (CA) University of Manchester United Kingdom (GB) Leiden University Netherlands (NL) University of Otago New Zealand (NZ) University of California Irvine United States (USA) (US) National Institute of Environmental Health Sciences (NIEHS) United States (USA) (US) King’s College London United Kingdom (GB) Robert-Bosch-Krankenhaus Germany (DE) Lund University / Lunds universitet Sweden (SE) Oulun Yliopisto / University of Oulo Finland (FI) Université Laval (UL) Canada (CA) Stanford University United States (USA) (US) IFOM - FIRC Institute of Molecular Oncology Italy (IT) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) General University Hospital of Larissa Greece (GR) Carmel Medical Center Israel (IL) Helsingin yliopisto / University of Helsinki Finland (FI) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) University of British Columbia Canada (CA) University General Hospital of Heraklion Greece (GR) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) American Cancer Society United States (USA) (US) Evangelische Kliniken Bonn gGmbH Germany (DE) Columbia University United States (USA) (US) University of Eastern Finland Finland (FI) Harvard University United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Acibadem Sistina Hospital Republic of North Macedonia (MK) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) City of Hope Medical Center United States (USA) (US)

How to cite

APA:

Dennis, J., Tyrer, J.P., Walker, L.C., Michailidou, K., Dorling, L., Bolla, M.K.,... Easton, D.F. (2022). Rare germline copy number variants (CNVs) and breast cancer risk. Communications Biology, 5(1), 65-. https://doi.org/10.1038/s42003-021-02990-6

MLA:

Dennis, Joe, et al. "Rare germline copy number variants (CNVs) and breast cancer risk." Communications Biology 5.1 (2022): 65-.

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