. 2022 Jan 18;5(1):65.

doi: 10.1038/s42003-021-02990-6.

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

Joe Dennis¹, Jonathan P Tyrer², Logan C Walker³, Kyriaki Michailidou^{4

5

6}, Leila Dorling⁴, Manjeet K Bolla⁴, Qin Wang⁴, Thomas U Ahearn⁷, Irene L Andrulis^{8

9}, Hoda Anton-Culver¹⁰, Natalia N Antonenkova¹¹, Volker Arndt¹², Kristan J Aronson¹³, Laura E Beane Freeman⁷, Matthias W Beckmann¹⁴, Sabine Behrens¹⁵, Javier Benitez^{16

17}, Marina Bermisheva¹⁸, Natalia V Bogdanova^{11

19

20}, Stig E Bojesen^{21

22

23}, Hermann Brenner^{12

24

25}, Jose E Castelao²⁶, Jenny Chang-Claude^{15

27}, Georgia Chenevix-Trench²⁸, Christine L Clarke²⁹; NBCS Collaborators; J Margriet Collée³⁰; CTS Consortium; Fergus J Couch³¹, Angela Cox³², Simon S Cross³³, Kamila Czene³⁴, Peter Devilee^{35

36}, Thilo Dörk²⁰, Laure Dossus³⁷, A Heather Eliassen^{38

39}, Mikael Eriksson³⁴, D Gareth Evans^{40

41}, Peter A Fasching^{14

42}, Jonine Figueroa^{7

43

44}, Olivia Fletcher⁴⁵, Henrik Flyger⁴⁶, Lin Fritschi⁴⁷, Marike Gabrielson³⁴, Manuela Gago-Dominguez^{48

49}, Montserrat García-Closas⁷, Graham G Giles^{50

51

52}, Anna González-Neira¹⁷, Pascal Guénel⁵³, Eric Hahnen^{54

55}, Christopher A Haiman⁵⁶, Per Hall^{34

57}, Antoinette Hollestelle⁵⁸, Reiner Hoppe^{59

60}, John L Hopper⁵¹, Anthony Howell⁶¹; ABCTB Investigators; kConFab/AOCS Investigators; Agnes Jager⁵⁸, Anna Jakubowska^{62

63}, Esther M John^{64

65}, Nichola Johnson⁴⁵, Michael E Jones⁶⁶, Audrey Jung¹⁵, Rudolf Kaaks¹⁵, Renske Keeman⁶⁷, Elza Khusnutdinova^{18

68}, Cari M Kitahara⁶⁹, Yon-Dschun Ko⁷⁰, Veli-Matti Kosma^{71

72

73}, Stella Koutros⁷, Peter Kraft^{39

74}, Vessela N Kristensen^{75

76}, Katerina Kubelka-Sabit⁷⁷, Allison W Kurian^{64

65}, James V Lacey^{78

79}, Diether Lambrechts^{80

81}, Nicole L Larson⁸², Martha Linet⁶⁹, Alicja Ogrodniczak⁶², Arto Mannermaa^{71

72

73}, Siranoush Manoukian⁸³, Sara Margolin^{57

84}, Dimitrios Mavroudis⁸⁵, Roger L Milne^{50

51

52}, Taru A Muranen⁸⁶, Rachel A Murphy^{87

88}, Heli Nevanlinna⁸⁶, Janet E Olson⁸², Håkan Olsson⁸⁹, Tjoung-Won Park-Simon²⁰, Charles M Perou⁹⁰, Paolo Peterlongo⁹¹, Dijana Plaseska-Karanfilska⁹², Katri Pylkäs^{93

94}, Gad Rennert⁹⁵, Emmanouil Saloustros⁹⁶, Dale P Sandler⁹⁷, Elinor J Sawyer⁹⁸, Marjanka K Schmidt^{67

99}, Rita K Schmutzler^{54

55

100}, Rana Shibli⁹⁵, Ann Smeets¹⁰¹, Penny Soucy¹⁰², Melissa C Southey^{50

52

103}, Anthony J Swerdlow^{66

104}, Rulla M Tamimi^{39

105}, Jack A Taylor^{97

106}, Lauren R Teras¹⁰⁷, Mary Beth Terry¹⁰⁸, Ian Tomlinson⁴⁴, Melissa A Troester¹⁰⁹, Thérèse Truong⁵³, Celine M Vachon¹¹⁰, Camilla Wendt⁸⁴, Robert Winqvist^{93

94}, Alicja Wolk^{111

112}, Xiaohong R Yang⁷, Wei Zheng¹¹³, Argyrios Ziogas¹⁰, Jacques Simard¹⁰², Alison M Dunning², Paul D P Pharoah^{4

2}, Douglas F Easton^{4

2}

Collaborators, Affiliations

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. jgd29@cam.ac.uk.
² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³ Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁶ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹¹ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
¹² Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹⁴ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany.
¹⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
¹⁷ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹⁸ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
¹⁹ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁰ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²¹ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²³ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
²⁷ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁸ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁹ Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
³⁰ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
³¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
³² Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
³³ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
³⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁵ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
³⁶ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³⁷ Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
³⁸ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁰ 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.
⁴¹ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁴² David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
⁴³ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁴⁴ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁴⁵ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
⁴⁶ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴⁷ School of Public Health, Curtin University, Perth, WA, Australia.
⁴⁸ 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.
⁴⁹ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁵⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁵¹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁵² Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁵³ Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, Villejuif, France.
⁵⁴ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁵ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵⁷ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁵⁸ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁵⁹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
⁶⁰ University of Tübingen, Tübingen, Germany.
⁶¹ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁶² Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁶³ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁶⁴ Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁶⁵ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁶⁶ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁶⁷ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁶⁸ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
⁶⁹ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁷⁰ Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.
⁷¹ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁷² Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁷³ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
⁷⁴ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷⁵ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁷⁶ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁷⁷ Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, Republic of North Macedonia.
⁷⁸ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
⁷⁹ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
⁸⁰ VIB Center for Cancer Biology, Leuven, Belgium.
⁸¹ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁸² Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁸³ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
⁸⁴ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁸⁵ Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
⁸⁶ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸⁷ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
⁸⁸ Cancer Control Research, BC Cancer, Vancouver, Canada.
⁸⁹ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
⁹⁰ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹¹ Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
⁹² Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
⁹³ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁹⁴ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
⁹⁵ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
⁹⁶ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
⁹⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
⁹⁸ School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
⁹⁹ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
¹⁰⁰ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰¹ Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium.
¹⁰² Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹⁰³ Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁰⁴ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹⁰⁵ Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
¹⁰⁶ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹⁰⁷ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
¹⁰⁸ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹⁰⁹ 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.
¹¹⁰ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
¹¹¹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹¹² Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹¹³ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

PMID: 35042965
PMCID: PMC8766486
DOI: 10.1038/s42003-021-02990-6

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

Joe Dennis et al. Commun Biol. 2022.

. 2022 Jan 18;5(1):65.

doi: 10.1038/s42003-021-02990-6.

Authors

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. jgd29@cam.ac.uk.
² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
³ Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁶ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹¹ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
¹² Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹⁴ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany.
¹⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁶ Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
¹⁷ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹⁸ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
¹⁹ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁰ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²¹ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²³ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
²⁷ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁸ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁹ Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
³⁰ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
³¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
³² Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
³³ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
³⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁵ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
³⁶ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³⁷ Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
³⁸ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁰ 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.
⁴¹ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁴² David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
⁴³ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁴⁴ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁴⁵ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
⁴⁶ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴⁷ School of Public Health, Curtin University, Perth, WA, Australia.
⁴⁸ 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.
⁴⁹ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁵⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁵¹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁵² Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁵³ Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, Villejuif, France.
⁵⁴ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁵ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵⁷ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁵⁸ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁵⁹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
⁶⁰ University of Tübingen, Tübingen, Germany.
⁶¹ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁶² Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁶³ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁶⁴ Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁶⁵ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁶⁶ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁶⁷ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁶⁸ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
⁶⁹ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁷⁰ Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.
⁷¹ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁷² Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁷³ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
⁷⁴ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷⁵ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁷⁶ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁷⁷ Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, Republic of North Macedonia.
⁷⁸ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
⁷⁹ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
⁸⁰ VIB Center for Cancer Biology, Leuven, Belgium.
⁸¹ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁸² Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁸³ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
⁸⁴ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
⁸⁵ Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
⁸⁶ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸⁷ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
⁸⁸ Cancer Control Research, BC Cancer, Vancouver, Canada.
⁸⁹ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
⁹⁰ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹¹ Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
⁹² Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
⁹³ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁹⁴ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
⁹⁵ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
⁹⁶ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
⁹⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
⁹⁸ School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
⁹⁹ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
¹⁰⁰ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁰¹ Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium.
¹⁰² Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹⁰³ Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁰⁴ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹⁰⁵ Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
¹⁰⁶ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹⁰⁷ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
¹⁰⁸ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹⁰⁹ 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.
¹¹⁰ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
¹¹¹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹¹² Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹¹³ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

PMID: 35042965
PMCID: PMC8766486
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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Flow diagram of the calling and analysis pipeline.**
CNVs were called using the CamCNV pipeline from the intensities from the iCOGs and OncoArray genotyping arrays. The CNVs were assigned to regions, association results generated for each array and then meta-analysed. CNVs covering the coding regions of genes were analysed in gene burden tests.

**Fig. 2. QQ plots of association results.**
Quantile-quantile plots of P-values from association tests of deletion regions (a), duplication regions (b), gene burden analysis for deletions (c), and gene burden for duplications (d).

**Fig. 3. Associations with duplications at the 17p13.3 locus.**
Log odds ratios for individual probes from Oncoarray and iCOGs are shown at the top in green. Genes from the Ensembl browser are shown in the next row, followed by structural variants identified by the 1000 Genomes Project with duplications in blue and deletions in red.

See this image and copyright information in PMC

References

1. Abel, H.J. et al. Mapping and characterization of structural variation in 17,795 human genomes. Nature583, 83–89 (2020). - PMC - PubMed
1. Collins RL, et al. A structural variation reference for medical and population genetics. Nature. 2020;581:444–451. doi: 10.1038/s41586-020-2287-8. - DOI - PMC - PubMed
1. Sudmant, P.H. et al. An integrated map of structural variation in 2,504 human genomes. Nature526, 75−81 (2015). - PMC - PubMed
1. Nik-Zainal S, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47–54. doi: 10.1038/nature17676. - DOI - PMC - PubMed
1. Gerstung M, et al. The evolutionary history of 2,658 cancers. Nature. 2020;578:122–128. doi: 10.1038/s41586-019-1907-7. - DOI - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous