. 2022 Nov 14;114(11):1533-1544.

doi: 10.1093/jnci/djac160.

Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Amber A DeVries¹, Joe Dennis², Jonathan P Tyrer³, Pei-Chen Peng¹, Simon G Coetzee¹, Alberto L Reyes¹, Jasmine T Plummer^{1

4}, Brian D Davis^{1

4}, Stephanie S Chen^{1

4}, Felipe Segato Dezem¹, Katja K H Aben^{5

6}, Hoda Anton-Culver⁷, Natalia N Antonenkova⁸, Matthias W Beckmann⁹, Alicia Beeghly-Fadiel¹⁰, Andrew Berchuck¹¹, Natalia V Bogdanova^{8

12

13}, Nadja Bogdanova-Markov¹⁴, James D Brenton¹⁵, Ralf Butzow¹⁶, Ian Campbell^{17

18}, Jenny Chang-Claude^{19

20}, Georgia Chenevix-Trench²¹, Linda S Cook^{22

23}, Anna DeFazio^{24

25

26}, Jennifer A Doherty²⁷, Thilo Dörk¹³, Diana M Eccles²⁸, A Heather Eliassen^{29

30

31}, Peter A Fasching^{9

32}, Renée T Fortner¹⁹, Graham G Giles^{33

34

35}, Ellen L Goode³⁶, Marc T Goodman³⁷, Jacek Gronwald³⁸; OPAL Study Group; AOCS Group; Niclas Håkansson³⁹, Michelle A T Hildebrandt⁴⁰, Chad Huff⁴⁰, David G Huntsman^{41

42}, Allan Jensen⁴³, Siddhartha Kar^{44

45}, Beth Y Karlan⁴⁶, Elza K Khusnutdinova^{47

48}, Lambertus A Kiemeney⁵, Susanne K Kjaer^{43

49}, Jolanta Kupryjanczyk⁵⁰, Marilyne Labrie⁵¹, Diether Lambrechts^{52

53}, Nhu D Le⁵⁴, Jan Lubiński³⁸, Taymaa May⁵⁵, Usha Menon⁵⁶, Roger L Milne^{33

34

35}, Francesmary Modugno^{57

58}, Alvaro N Monteiro⁵⁹, Kirsten B Moysich⁶⁰, Kunle Odunsi^{61

62}, Håkan Olsson⁶³, Celeste L Pearce^{64

65}, Tanja Pejovic^{53

66}, Susan J Ramus^{67

68}, Elio Riboli⁶⁹, Marjorie J Riggan¹¹, Isabelle Romieu⁷⁰, Dale P Sandler⁷¹, Joellen M Schildkraut⁷², V Wendy Setiawan⁷³, Weiva Sieh^{74

75}, Honglin Song⁷⁶, Rebecca Sutphen⁷⁷, Kathryn L Terry^{30

78}, Pamela J Thompson³⁷, Linda Titus⁷⁹, Shelley S Tworoger⁵⁹, Els Van Nieuwenhuysen⁸⁰, Digna Velez Edwards⁸¹, Penelope M Webb⁸², Nicolas Wentzensen⁸³, Alice S Whittemore^{84

85}, Alicja Wolk^{39

86}, Anna H Wu⁶⁵, Argyrios Ziogas⁷, Matthew L Freedman⁸⁷, Kate Lawrenson⁸⁸, Paul D P Pharoah^{2

3}, Douglas F Easton^{2

3}, Simon A Gayther¹, Michelle R Jones¹

Collaborators, Affiliations

Collaborators

P Webb, A DeFazio, M Friedlander, A Obermair, P Grant, C Nagle, V Beesley, G Chevenix-Trench, D Bowtell, P Blomfield, A Brand, A Davis, Y Leung, J Nicklin, M Quinn, K Livingstone, H O'Neill, M Williams, A Black, A Hadley, A Glasgow, A Garrett, A Rao, C Shannon, C Steer, D Allen, D Neesham, G Otton, G Au-Yeung, G Goss, G Wain, G Gard, G Robertson, J Lombard, J Tan, J McNeilage, J Power, J Coward, J Miller, J Carter, J Lamont, K M Wong, K Reid, L Perrin, L Milishkin, M Nascimento, M Buck, M Bunting, M Harrison, N Chetty, N Hacker, O McNally, P Harnett, P Beale, R Awad, R Mohan, R Farrell, R McIntosh, R Rome, R Sayer, R Houghton, R Hogg, R Land, S Baron-Hay, S Paramasivum, S Pather, S Hyde, S Salfinger, S Valmadre, T Jobling, T Manolitsas, T Bonaventura, V Arora, D Bowtell, G Chenevix-Trench, A Green, P Webb, A DeFazio, D Gertig, N Traficante, S Fereday, S Moore, J Hung, K Harrap, T Sadkowsky, N Pandeya, M Malt, R Robertson, T Vanden Bergh, M Jones, P McKenzie, J Maidens, K Nattress, Y E Chiew, A Stenlake, H Sullivan, B Alexander, P Ashover, S Brown, T Corrish, L Green, L Jackman, K Ferguson, K Martin, A Martyn, B Ranieri, J White, V Jayde, L Bowes, P Mamers, L Galletta, D Giles, J Hendley, K Alsop, T Schmidt, H Shirley, C Ball, C Young, S Viduka, H Tran, S Bilic, L Glavinas, J Brooks, R Stuart-Harris, F Kirsten, J Rutovitz, P Clingan, A Glasgow, A Proietto, S Braye, G Otton, J Shannon, T Bonaventura, J Stewart, S Begbie

Affiliations

¹ Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴ Applied Genomics, Computation and Translational Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵ Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
⁶ Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
⁷ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
⁸ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
⁹ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
¹⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹¹ Department of Gynecologic Oncology, Duke University Hospital, Durham, NC, USA.
¹² Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
¹³ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
¹⁴ Institute of Human Genetics, University of Münster, Münster, Germany.
¹⁵ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
¹⁶ Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹⁷ Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
¹⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²² Epidemiology, School of Public Health, University of Colorado, Aurora, CO, USA.
²³ Community Health Sciences, University of Calgary, Calgary, AB, Canada.
²⁴ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.
²⁵ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
²⁶ The Daffodil Centre, a joint venture with Cancer Council NSW, The University of Sydney, Sydney, New South Wales, Australia.
²⁷ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
²⁸ Faculty of Medicine, University of Southampton, Southampton, UK.
²⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³¹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³² David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
³³ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
³⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁵ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
³⁶ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
³⁷ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³⁸ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴⁰ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴¹ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁴² Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
⁴³ Department of Lifestyle, Reproduction and Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark.
⁴⁴ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁴⁵ Section of Translational Epidemiology, Division of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁴⁶ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
⁴⁷ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
⁴⁸ Saint Petersburg State University, Saint Petersburg, Russia.
⁴⁹ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁵⁰ Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
⁵¹ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁵² VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁵³ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁵⁴ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
⁵⁵ Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada.
⁵⁶ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁵⁷ Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
⁵⁸ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵⁹ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
⁶⁰ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
⁶¹ Department of Oncology, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.
⁶² Department of Obstetrics and Gynecology, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.
⁶³ Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁶⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
⁶⁶ Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA.
⁶⁷ School of Women's and Children's Health, Faculty of Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
⁶⁸ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁶⁹ Imperial College London, London, UK.
⁷⁰ Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
⁷¹ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
⁷² Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁷³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷⁴ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷⁶ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷⁷ Epidemiology Center, College of Medicine, University of South Florida, Tampa, FL, USA.
⁷⁸ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁷⁹ Muskie School of Public Policy, Public Health, Portland, ME, USA.
⁸⁰ Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Leuven Cancer Institute, Leuven, Belgium.
⁸¹ Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Department of Biomedical Sciences, Women's Health Research, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸² Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁸⁴ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁸⁵ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁸⁶ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁸⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸⁸ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Women's Cancer Program at the Samuel Oschin Cancer Institute Cedars-Sinai Medical Center, Los Angeles, CA, USA.

PMID: 36210504
PMCID: PMC9949586
DOI: 10.1093/jnci/djac160

Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Amber A DeVries et al. J Natl Cancer Inst. 2022.

. 2022 Nov 14;114(11):1533-1544.

doi: 10.1093/jnci/djac160.

Authors

Collaborators

P Webb, A DeFazio, M Friedlander, A Obermair, P Grant, C Nagle, V Beesley, G Chevenix-Trench, D Bowtell, P Blomfield, A Brand, A Davis, Y Leung, J Nicklin, M Quinn, K Livingstone, H O'Neill, M Williams, A Black, A Hadley, A Glasgow, A Garrett, A Rao, C Shannon, C Steer, D Allen, D Neesham, G Otton, G Au-Yeung, G Goss, G Wain, G Gard, G Robertson, J Lombard, J Tan, J McNeilage, J Power, J Coward, J Miller, J Carter, J Lamont, K M Wong, K Reid, L Perrin, L Milishkin, M Nascimento, M Buck, M Bunting, M Harrison, N Chetty, N Hacker, O McNally, P Harnett, P Beale, R Awad, R Mohan, R Farrell, R McIntosh, R Rome, R Sayer, R Houghton, R Hogg, R Land, S Baron-Hay, S Paramasivum, S Pather, S Hyde, S Salfinger, S Valmadre, T Jobling, T Manolitsas, T Bonaventura, V Arora, D Bowtell, G Chenevix-Trench, A Green, P Webb, A DeFazio, D Gertig, N Traficante, S Fereday, S Moore, J Hung, K Harrap, T Sadkowsky, N Pandeya, M Malt, R Robertson, T Vanden Bergh, M Jones, P McKenzie, J Maidens, K Nattress, Y E Chiew, A Stenlake, H Sullivan, B Alexander, P Ashover, S Brown, T Corrish, L Green, L Jackman, K Ferguson, K Martin, A Martyn, B Ranieri, J White, V Jayde, L Bowes, P Mamers, L Galletta, D Giles, J Hendley, K Alsop, T Schmidt, H Shirley, C Ball, C Young, S Viduka, H Tran, S Bilic, L Glavinas, J Brooks, R Stuart-Harris, F Kirsten, J Rutovitz, P Clingan, A Glasgow, A Proietto, S Braye, G Otton, J Shannon, T Bonaventura, J Stewart, S Begbie

Affiliations

¹ Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴ Applied Genomics, Computation and Translational Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵ Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
⁶ Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
⁷ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
⁸ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
⁹ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
¹⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹¹ Department of Gynecologic Oncology, Duke University Hospital, Durham, NC, USA.
¹² Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
¹³ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
¹⁴ Institute of Human Genetics, University of Münster, Münster, Germany.
¹⁵ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
¹⁶ Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹⁷ Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
¹⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²² Epidemiology, School of Public Health, University of Colorado, Aurora, CO, USA.
²³ Community Health Sciences, University of Calgary, Calgary, AB, Canada.
²⁴ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.
²⁵ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
²⁶ The Daffodil Centre, a joint venture with Cancer Council NSW, The University of Sydney, Sydney, New South Wales, Australia.
²⁷ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
²⁸ Faculty of Medicine, University of Southampton, Southampton, UK.
²⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³¹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³² David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
³³ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
³⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁵ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
³⁶ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
³⁷ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³⁸ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴⁰ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴¹ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁴² Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
⁴³ Department of Lifestyle, Reproduction and Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark.
⁴⁴ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁴⁵ Section of Translational Epidemiology, Division of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁴⁶ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
⁴⁷ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
⁴⁸ Saint Petersburg State University, Saint Petersburg, Russia.
⁴⁹ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁵⁰ Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
⁵¹ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁵² VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁵³ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁵⁴ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
⁵⁵ Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada.
⁵⁶ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁵⁷ Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
⁵⁸ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵⁹ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
⁶⁰ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
⁶¹ Department of Oncology, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.
⁶² Department of Obstetrics and Gynecology, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.
⁶³ Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁶⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
⁶⁶ Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA.
⁶⁷ School of Women's and Children's Health, Faculty of Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
⁶⁸ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁶⁹ Imperial College London, London, UK.
⁷⁰ Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
⁷¹ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
⁷² Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
⁷³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷⁴ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷⁶ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷⁷ Epidemiology Center, College of Medicine, University of South Florida, Tampa, FL, USA.
⁷⁸ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁷⁹ Muskie School of Public Policy, Public Health, Portland, ME, USA.
⁸⁰ Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Leuven Cancer Institute, Leuven, Belgium.
⁸¹ Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Department of Biomedical Sciences, Women's Health Research, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸² Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁸⁴ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁸⁵ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁸⁶ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁸⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸⁸ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Women's Cancer Program at the Samuel Oschin Cancer Institute Cedars-Sinai Medical Center, Los Angeles, CA, USA.

PMID: 36210504
PMCID: PMC9949586
DOI: 10.1093/jnci/djac160

Abstract

Background: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.

Methods: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types.

Results: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.

Conclusions: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

PubMed Disclaimer

Figures

**Figure 1.**
CNVs identified at the *BRCA1*, *BRCA2*, and *RAD51C* susceptibility gene risk loci in EOC cases and controls. CNVs of varying size predicting deletions (**horizontal red bars**) and duplications (**horizontal blue bars**) in EOC cases (**solid bars**) and controls (**faint bars**) at the **(A)** *BRCA1*, **(B)** *BRCA2*, and **(C)** *RAD51C* gene loci. The location of all probes genotyped on the Illumina OncoArray and used to “call” copy number variations are shown as **vertical blue lines**. CNV = copy number variants.

**Figure 2.**
A) Manhattan plots showing the results of single-probe CNV association testing. At a Bonferroni P value cutoff (**blue line**) of P < 8.71E-7 for the all EOC cases (based on 57 432 tests) and P < 8.56E-7 for HGSOC cases only (based on 58 382 tests) identified statistically significant probes at the BRCA1 gene locus. Evidence of several additional risk associations with a Bonferroni P value cutoff of P < 5E-4, including associations at intergenic sites, are also shown. B) Manhattan plot displaying results of common CNV analysis. At a Bonferroni P value cutoff of P < 2.09E-6 based on 23 960 tag SNPs included in the lookup, we identified statistically significant SNPs at 4 loci. At these loci, there are common CNVs in high linkage disequilibrium with GWAS SNPs that may account for some of the variation leading to differences in risk at that SNP. CNV = copy number variants; EOC = epithelial ovarian cancer; GWAS = genome-wide association studies; HGSOC = high-grade serous ovarian cancer; SNP = single nucleotide variants.

**Figure 3.**
Enrichment of EOC statistically significant CNVs (P < .05) in functional biofeatures in ovarian cancer–related cell types. EOC risk CNVs are statistically significantly enriched in insulators across all ovarian cancer–relevant histotype consensus groups. The total number of risk CNVs in each biofeature per histotype grouping can be found in Supplementary Table 11 (available online). Abbreviations for histotypes are as follows: CCOC = clear cell ovarian cancer; EEC = endometriosis (precursor cell type); FT = fallopian tube secretory epithelial cells (precursor cell type); HGSOC = high-grade serous ovarian cancer; IOSE = immortalized ovarian surface epithelium (precursor cell type); LGSOC = low-grade serous ovarian cancer; MOC = mucinous ovarian cancer. CNV = copy number variants; EOC = epithelial ovarian cancer.

See this image and copyright information in PMC

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Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

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Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

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