Rare germline copy number variants (CNVs) and breast cancer risk.
About this Publication
Title
Rare germline copy number variants (CNVs) and breast cancer risk.
Pubmed ID
35042965
(View this publication on the PubMed website)
Digital Object Identifier
Publication
Commun Biol. 2022 Jan 18; Volume 5 (Issue 1): Pages 65
Authors
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
, ...show more Brenner H
, Castelao JE
, Chang-Claude J
, Chenevix-Trench G
, Clarke CL
, NBCS Collaborators
, Collée JM
, CTS Consortium
, Couch FJ
, Cox A
, 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 YD
, Kosma VM
, 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 TW
, 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
Affiliations
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. jgd29@cam.ac.uk.
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
- Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
- Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
- Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
- N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
- Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
- Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
- Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
- Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
- Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
- Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
- Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
- School of Public Health, Curtin University, Perth, WA, Australia.
- Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
- Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, Villejuif, France.
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
- Division of Cancer Sciences, University of Manchester, Manchester, UK.
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
- Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
- Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
- Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.
- Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
- Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, Republic of North Macedonia.
- Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
- VIB Center for Cancer Biology, Leuven, Belgium.
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
- Department of Oncology, Södersjukhuset, Stockholm, Sweden.
- Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
- School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
- Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
- Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
- Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
- Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
- Department of Oncology, University Hospital of Larissa, Larissa, Greece.
- Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
- School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
- Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium.
- Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
- Department of Population Science, American Cancer Society, Atlanta, GA, USA.
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
- Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
- Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
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.
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