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