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

Author:

DeVries Amber A1,Dennis Joe2ORCID,Tyrer Jonathan P3,Peng Pei-Chen1,Coetzee Simon G1,Reyes Alberto L1,Plummer Jasmine T14ORCID,Davis Brian D14,Chen Stephanie S14,Dezem Felipe Segato1,Aben Katja K H56,Anton-Culver Hoda7ORCID,Antonenkova Natalia N8,Beckmann Matthias W9,Beeghly-Fadiel Alicia10,Berchuck Andrew11,Bogdanova Natalia V81213,Bogdanova-Markov Nadja14,Brenton James D15,Butzow Ralf16,Campbell Ian1718ORCID,Chang-Claude Jenny1920,Chenevix-Trench Georgia21ORCID,Cook Linda S2223,DeFazio Anna242526,Doherty Jennifer A27,Dörk Thilo13,Eccles Diana M28,Eliassen A Heather293031ORCID,Fasching Peter A932,Fortner Renée T19,Giles Graham G333435,Goode Ellen L36,Goodman Marc T37,Gronwald Jacek38,Webb PORCID,DeFazio A,Friedlander M,Obermair A,Grant P,Nagle C,Beesley V,Chevenix-Trench G,Bowtell D,Blomfield P,Brand A,Davis A,Leung Y,Nicklin J,Quinn M,Livingstone K,O'Neill H,Williams M,Black A,Hadley A,Glasgow A,Garrett A,Rao A,Shannon C,Steer C,Allen D,Neesham D,Otton G,Au-Yeung G,Goss G,Wain G,Gard G,Robertson G,Lombard J,Tan J,McNeilage J,Power J,Coward J,Miller J,Carter J,Lamont J,Wong K M,Reid K,Perrin L,Milishkin L,Nascimento M,Buck M,Bunting M,Harrison M,Chetty N,Hacker N,McNally O,Harnett P,Beale P,Awad R,Mohan R,Farrell R,McIntosh R,Rome R,Sayer R,Houghton R,Hogg R,Land R,Baron-Hay S,Paramasivum S,Pather S,Hyde S,Salfinger S,Valmadre S,Jobling T,Manolitsas T,Bonaventura T,Arora V,Bowtell D,Chenevix-Trench G,Green A,Webb P,DeFazio A,Gertig D,Traficante N,Fereday S,Moore S,Hung J,Harrap K,Sadkowsky T,Pandeya N,Malt M,Robertson R,Bergh T Vanden,Jones MORCID,McKenzie P,Maidens J,Nattress K,Chiew Y E,Stenlake A,Sullivan H,Alexander B,Ashover P,Brown S,Corrish T,Green L,Jackman L,Ferguson K,Martin K,Martyn A,Ranieri B,White J,Jayde V,Bowes L,Mamers P,Galletta L,Giles D,Hendley J,Alsop K,Schmidt T,Shirley H,Ball C,Young C,Viduka S,Tran H,Bilic S,Glavinas L,Brooks J,Stuart-Harris R,Kirsten F,Rutovitz J,Clingan P,Glasgow A,Proietto A,Braye S,Otton G,Shannon J,Bonaventura T,Stewart J,Begbie S,Håkansson Niclas39,Hildebrandt Michelle A T40,Huff Chad40,Huntsman David G4142,Jensen Allan43ORCID,Kar Siddhartha4445ORCID,Karlan Beth Y46,Khusnutdinova Elza K4748,Kiemeney Lambertus A5,Kjaer Susanne K4349,Kupryjanczyk Jolanta50,Labrie Marilyne51,Lambrechts Diether5253,Le Nhu D54,Lubiński Jan38,May Taymaa55,Menon Usha56ORCID,Milne Roger L333435,Modugno Francesmary5758,Monteiro Alvaro N59,Moysich Kirsten B60,Odunsi Kunle6162,Olsson Håkan63,Pearce Celeste L6465,Pejovic Tanja5366,Ramus Susan J6768,Riboli Elio69ORCID,Riggan Marjorie J11,Romieu Isabelle70,Sandler Dale P71,Schildkraut Joellen M72,Setiawan V Wendy73,Sieh Weiva7475ORCID,Song Honglin76,Sutphen Rebecca77,Terry Kathryn L3078,Thompson Pamela J37,Titus Linda79,Tworoger Shelley S59,Van Nieuwenhuysen Els80,Edwards Digna Velez81,Webb Penelope M82ORCID,Wentzensen Nicolas83ORCID,Whittemore Alice S8485,Wolk Alicja3986ORCID,Wu Anna H65,Ziogas Argyrios7ORCID,Freedman Matthew L87,Lawrenson Kate88ORCID,Pharoah Paul D P23,Easton Douglas F23,Gayther Simon A1,Jones Michelle R1ORCID, ,

Affiliation:

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

Abstract

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.

Funder

National Institute of General Medical Sciences

National Institutes of Health

CSMC Precision Health Initiative

Tell Every Amazing Lady About Ovarian Cancer Louisa M. McGregor Ovarian Cancer Foundation

Ovarian Cancer Research Fund thanks

National Cancer Institute

Wellcome Trust

National Human Genome Research Institute

Canadian Institutes of Health Research

Ovarian Cancer Research Fund

European Commission’s Seventh Framework Programme

Army Medical Research and Materiel Command

National Health & Medical Research Council of Australia

Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia

Ovarian Cancer Australia

Peter MacCallum Foundation

University of Erlangen-Nuremberg

National Kankerplan

Breast Cancer Now, Institute of Cancer Research

National Center for Advancing Translational Sciences

European Commission

International Agency for Research on Cancer

Danish Cancer Society

Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale

Institut National de la Santé et de la Recherche Médicale

German Cancer Aid; German Cancer Research Center

Federal Ministry of Education and Research

Hellenic Health Foundation

Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy

National Research Council

Dutch Ministry of Public Health, Welfare and Sports

Netherlands Cancer Registry

LK Research Funds

Dutch Prevention Funds

World Cancer Research Fund

Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health

Health Research Fund

Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra

Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten

Cancer Research UK

Medical Research Council

German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research

German Cancer Research Center

Rudolf-Bartling Foundation

Helsinki University Hospital Research Fund

University of Pittsburgh School of Medicine Dean’s Faculty Advancement Award

Department of Defense

NCI

Swedish Cancer Society, Swedish Research Council, Beta Kamprad Foundation

Danish Cancer Society, Copenhagen

Mayo Foundation

Minnesota Ovarian Cancer Alliance

Fred C. and Katherine B. Andersen Foundation

VicHealth and Cancer Council Victoria, Cancer Council Victoria

National Health and Medical Research Council of Australia

NHMRC

DOD Ovarian Cancer Research Program

Moffitt Cancer Center

Merck Pharmaceuticals

Radboud University Medical Centre

UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge

National Institute of Environmental Health Sciences

The Swedish Cancer Foundation

the Swedish Research Council

American Cancer Society

Celma Mastry Ovarian Cancer Foundation

Lon V Smith Foundation

The Eve Appeal

National Institute for Health Research University College London Hospitals Biomedical Research Centre

California Cancer Research Program

National Science Centre

NIH

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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