Letter | Published:

Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Nature Genetics volume 47, pages 164171 (2015) | Download Citation

Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10−8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

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Acknowledgements

We thank all the individuals who took part in this study and all the researchers, clinicians, and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note), including X.Q. Chen for iPLEX genotyping. The COGS project is funded through a European Commission Seventh Framework Programme grant (agreement number 223175-HEALTH-F2-2009-223175). CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). Scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control Consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based on data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the US National Cancer Institute and US National Human Genome Research Institute (database of Genotypes and Phenotypes (dbGaP) accession phs000178.v8.p7). The cBio Portal is developed and maintained by the Computational Biology Center at the Memorial Sloan-Kettering Cancer Center. S. Healey is supported by a National Health and Medical Research Council of Australia Program Grant to G.C.-T. Details of the funding of individual investigators and studies are provided in the Supplementary Note. A full list of the investigators who contributed to the generation of the data is available on the CIMBA website (see URLs).

Author information

Author notes

    • Karoline B Kuchenbaecker
    • , Susan J Ramus
    •  & Jonathan Tyrer

    These authors contributed equally to this work.

    • Antonis C Antoniou
    •  & Georgia Chenevix-Trench

    These authors jointly supervised this work.

Affiliations

  1. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Karoline B Kuchenbaecker
    • , Andrew Lee
    • , Lesley McGuffog
    • , Daniel Barrowdale
    • , Joe Dennis
    • , Debra Frost
    • , Jo Perkins
    • , Radka Platte
    • , Steve Ellis
    •  & Douglas F Easton
  2. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.

    • Susan J Ramus
    • , Howard C Shen
    • , Kate Lawrenson
    • , Janet M Lee
    • , Tassja J Spindler
    • , Dennis Hazelett
    • , Alice W Lee
    • , Anna H Wu
    • , Celeste L Pearce
    • , Gerry Coetzee
    • , Malcolm C Pike
    •  & Simon Gayther
  3. Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

    • Jonathan Tyrer
    • , Joe Dennis
    • , Ed Dicks
    • , Helen Baker
    • , Honglin Song
    • , Patricia Harrington
    •  & Paul P Pharoah
  4. Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Jonathan Beesley
    • , Sue Healey
    •  & Georgia Chenevix-Trench
  5. Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA.

    • Yvonne G Lin
  6. Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, USA.

    • Tanja Pejovic
    • , Yukie Bean
    •  & Melissa Kellar
  7. Knight Cancer Institute, Portland, Oregon, USA.

    • Tanja Pejovic
    • , Yukie Bean
    •  & Melissa Kellar
  8. Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Qiyuan Li
    •  & Matt Freedman
  9. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.

    • Simon Coetzee
    •  & Houtan Noushmehr
  10. Center for Cell-Based Therapy, Monte Alegre, Ribeirão Preto, Brazil.

    • Simon Coetzee
  11. Center for Integrative Systems Biology, Monte Alegre, Ribeirão Preto, Brazil.

    • Simon Coetzee
  12. Department of Urology, University of Southern California, Los Angeles, California, USA.

    • Dennis Hazelett
    •  & Gerry Coetzee
  13. Department of Genomics and Genome Sciences, Case Western Reserve University Medical School, Cleveland, Ohio, USA.

    • Alexander Miron
  14. Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.

    • Melissa Southey
  15. Department of Epidemiology, Columbia University, New York, New York, USA.

    • Mary Beth Terry
  16. Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • David E Goldgar
  17. Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Saundra S Buys
  18. Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medical Center, Vilinius University Hospital Santariskiu Clinics, Vilnius, Lithuania, Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania.

    • Ramunas Janavicius
  19. State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.

    • Ramunas Janavicius
  20. Department of Genetics, University of Pretoria, Pretoria, South Africa.

    • Cecilia M Dorfling
    •  & Elizabeth J van Rensburg
  21. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.

    • Susan L Neuhausen
    •  & Yuan Chun Ding
  22. Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • Thomas V O Hansen
    •  & Lars Jønson
  23. Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • Anne-Marie Gerdes
  24. Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • Bent Ejlertsen
  25. Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.

    • Javier Benitez
    • , Ana Osorio
    •  & Maria Jose Garcia
  26. Human Genotyping Unit (CEGEN), Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.

    • Javier Benitez
  27. Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.

    • Javier Benitez
    • , Ana Osorio
    •  & Maria Jose Garcia
  28. Maricopa Medical Center, care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California, USA.

    • Ian Komenaka
  29. Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California, USA.

    • Jeffrey N Weitzel
  30. Cook County Health and Hospital System, care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California, USA.

    • Pamela Ganschow
  31. Fondazione Istituto FIRC (Italian Foundation for Cancer Research) di Oncologia Molecolare (IFOM), Milan, Italy.

    • Paolo Peterlongo
  32. Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.

    • Loris Bernard
  33. Cogentech Cancer Genetic Test Laboratory, Milan, Italy.

    • Loris Bernard
  34. Division of Experimental Oncology, CRO (Centro di Riferimento Oncologico) Aviano National Cancer Institute, Aviano, Italy.

    • Alessandra Viel
  35. Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.

    • Bernardo Bonanni
  36. Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico (Italian Research Hospital)) Istituto Nazionale Tumori (INT), Milan, Italy.

    • Bernard Peissel
    •  & Siranoush Manoukian
  37. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.

    • Paolo Radice
  38. Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.

    • Laura Papi
  39. Department of Molecular Medicine, University La Sapienza, Rome, Italy.

    • Laura Ottini
  40. Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology), National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens, Greece.

    • Florentia Fostira
    •  & Irene Konstantopoulou
  41. Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Judy Garber
  42. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.

    • Andrew K Godwin
  43. Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Cologne, Germany.

    • Rita Katharina Schmutzler
  44. Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.

    • Rita Katharina Schmutzler
  45. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.

    • Rita Katharina Schmutzler
  46. On behalf of the German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC).

    • Rita Katharina Schmutzler
  47. Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

    • Alfons Meindl
  48. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

    • Christoph Engel
  49. Institute of Human Genetics, University Heidelberg, Heidelberg, Germany.

    • Christian Sutter
  50. INSERM U1052, CNRS UMR 5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France.

    • Olga M Sinilnikova
    • , Francesca Damiola
    •  & Sylvie Mazoyer
  51. Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon–Centre Léon Bérard, Lyon, France.

    • Olga M Sinilnikova
  52. Institut Curie, Department of Tumour Biology, Paris, France.

    • Dominique Stoppa-Lyonnet
  53. Institut Curie, INSERM U830, Paris, France.

    • Dominique Stoppa-Lyonnet
  54. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

    • Dominique Stoppa-Lyonnet
  55. Center for Medical Genetics, Ghent University, Ghent, Belgium.

    • Kathleen Claes
    •  & Kim De Leeneer
  56. Australia New Zealand Gynecologic Oncology Group (ANZGOG) and Familial Cancer Service, Westmead Hosptial, Sydney, New South Wales, Australia.

    • Judy Kirk
  57. Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, USA.

    • Gustavo C Rodriguez
  58. Gynecologic Oncology Group, Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Marion Piedmonte
  59. James Cancer Center, Ohio State University, Columbus, Ohio, USA.

    • David M O'Malley
  60. Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.

    • Miguel de la Hoya
    •  & Trinidad Caldes
  61. Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.

    • Kristiina Aittomäki
  62. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

    • Heli Nevanlinna
    • , Arto Leminen
    • , Liisa M Pelttari
    •  & Ralf Butzow
  63. Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • J Margriet Collée
  64. Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

    • Matti A Rookus
  65. Department of Genetics, University Medical Center, Groningen University, Groningen, the Netherlands.

    • Jan C Oosterwijk
  66. Latvian Biomedical Research and Study Centre, Riga, Latvia.

    • Laima Tihomirova
  67. Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

    • Nadine Tung
  68. Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.

    • Ute Hamann
  69. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

    • Claudine Isaccs
  70. Program in Cancer Genetics, McGill University, Montreal, Quebec, Canada.

    • Marc Tischkowitz
  71. N.N. Petrov Institute of Oncology, St. Petersburg, Russia.

    • Evgeny N Imyanitov
  72. Section of Genetic Oncology, Department of Laboratory Medicine, University of Pisa and University Hospital of Pisa, Pisa, Italy.

    • Maria A Caligo
  73. VBCRC (Victorian Breast Cancer Research Consortium) Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

    • Ian G Campbell
  74. Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, the Netherlands.

    • Frans B L Hogervorst
  75. Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.

    • Edith Olah
  76. Oncogenetics Group, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO) and Universitat Autònoma de Barcelona, Barcelona, Spain.

    • Orland Diez
  77. Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute)–Catalan Institute of Oncology, Barcelona, Spain.

    • Ignacio Blanco
  78. Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona)–Catalan Institute of Oncology, Girona, Spain.

    • Joan Brunet
  79. Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL–Catalan Institute of Oncology, Barcelona, Spain.

    • Conxi Lazaro
    •  & Miquel Angel Pujana
  80. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

    • Anna Jakubowska
    • , Jacek Gronwald
    • , Jan Lubinski
    •  & Grzegorz Sukiennicki
  81. Department of Pathology, Landspitali University Hospital and Biomedical Centre (BMC), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Rosa B Barkardottir
  82. Gynaecologic Oncology Service, Centre Hospitalier Universitaire de Québec (CHUQ), Quebec City, Quebec, Canada.

    • Marie Plante
  83. Centre Hospitalier Universitaire de Québec (CHUQ) Research Center, Laval University, Quebec City, Quebec, Canada.

    • Jacques Simard
    •  & Penny Soucy
  84. Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto (IOV)-IRCCS, Padua, Italy.

    • Marco Montagna
    •  & Silvia Tognazzo
  85. Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.

    • Manuel R Teixeira
  86. Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.

    • Manuel R Teixeira
  87. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Vernon S Pankratz
    • , Noralane Lindor
    • , Ellen L Goode
    •  & Fergus J Couch
  88. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Xianshu Wang
    • , Julie M Cunningham
    •  & Fergus J Couch
  89. National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Csilla I Szabo
  90. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Noah Kauff
    • , Joseph Vijai
    • , Carol A Aghajanian
    •  & Kenneth Offit
  91. Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

    • Georg Pfeiler
    • , Andreas Berger
    • , Christian F Singer
    •  & Muy-Kheng Tea
  92. Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.

    • Catherine M Phelan
    • , Alvaro N Monteiro
    • , Jenny Permuth-Wey
    • , Thomas A Sellers
    •  & Ya-Yu Tsai
  93. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland, USA.

    • Mark H Greene
    •  & Phuong L Mai
  94. Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel.

    • Gad Rennert
  95. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

    • Anna Marie Mulligan
    •  & Irene L Andrulis
  96. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.

    • Anna Marie Mulligan
  97. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Irene L Andrulis
  98. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Sandrine Tchatchou
    •  & Gord Glendon
  99. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio, USA.

    • Amanda Ewart Toland
  100. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.

    • Uffe Birk Jensen
  101. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

    • Torben A Kruse
    •  & Mads Thomassen
  102. Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.

    • Anders Bojesen
  103. Institute of Oncology, Rivka Ziv Medical Center, Zefat, Israel.

    • Jamal Zidan
  104. Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel Aviv, Israel.

    • Eitan Friedman
    •  & Yael Laitman
  105. Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.

    • Maria Soller
  106. Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.

    • Annelie Liljegren
    •  & Brita Arver
  107. Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.

    • Zakaria Einbeigi
  108. Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

    • Marie Stenmark-Askmalm
  109. Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, USA.

    • Olufunmilayo I Olopade
  110. Department of Medicine and Genetics, University of California, San Francisco, San Francisco, California, USA.

    • Robert L Nussbaum
  111. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Timothy R Rebbeck
    • , Katherine L Nathanson
    •  & Susan M Domchek
  112. Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Karen H Lu
  113. Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Beth Y Karlan
    • , Christine Walsh
    • , Jenny Lester
    •  & Sandra Orsulic
  114. Department of Obstetrics and Gynecology, Erlangen University Hospital, University of Erlangen-Nuremberg, Erlangen, Germany.

    • Alexander Hein
    • , Matthias W Beckmann
    •  & Peter A Fasching
  115. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.

    • Arif B Ekici
  116. Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Peter A Fasching
  117. Vesalius Research Center, VIB, Leuven, Belgium.

    • Diether Lambrechts
  118. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
  119. Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.

    • Els Van Nieuwenhuysen
    • , Ignace Vergote
    •  & Sandrina Lambrechts
  120. Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.

    • Jennifer A Doherty
  121. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Kristine G Wicklund
    •  & Mary Anne Rossing
  122. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Mary Anne Rossing
  123. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Anja Rudolph
    • , Jenny Chang-Claude
    •  & Ursula Eilber
  124. Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.

    • Shan Wang-Gohrke
  125. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Kirsten B Moysich
    • , Lara Sucheston
    •  & Shashi Lele
  126. Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Kunle Odunsi
  127. Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

    • Lynne R Wilkens
    •  & Yurii B Shvetsov
  128. Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Marc T Goodman
    •  & Pamela J Thompson
  129. Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Marc T Goodman
    •  & Pamela J Thompson
  130. Department of Gynecology, Jena University Hospital–Friedrich Schiller University, Jena, Germany.

    • Ingo B Runnebaum
    •  & Matthias Dürst
  131. Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.

    • Peter Hillemanns
  132. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

    • Thilo Dörk
    •  & Natalia Bogdanova
  133. Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.

    • Natalia Antonenkova
  134. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland.

    • Ralf Butzow
  135. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Francesmary Modugno
  136. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Francesmary Modugno
    • , Joseph L Kelley
    •  & Robert P Edwards
  137. Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Francesmary Modugno
    •  & Robert P Edwards
  138. Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.

    • Francesmary Modugno
  139. University of Texas School of Public Health, Houston, Texas, USA.

    • Roberta B Ness
  140. Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.

    • Andreas du Bois
    • , Florian Heitz
    •  & Philipp Harter
  141. Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.

    • Andreas du Bois
    • , Florian Heitz
    •  & Philipp Harter
  142. Institut für Humangenetik Wiesbaden, Wiesbaden, Germany.

    • Ira Schwaab
  143. Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.

    • Keitaro Matsuo
  144. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.

    • Satoyo Hosono
  145. Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.

    • Allan Jensen
    • , Susanne Kruger Kjaer
    •  & Estrid Hogdall
  146. Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

    • Susanne Kruger Kjaer
    • , Claus Hogdall
    •  & Lene Lundvall
  147. Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.

    • Estrid Hogdall
  148. Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.

    • Hanis Nazihah Hasmad
    •  & Soo-Hwang Teo
  149. Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.

    • Mat Adenan Noor Azmi
    •  & Yin-Ling Woo
  150. University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.

    • Soo-Hwang Teo
    •  & Yin-Ling Woo
  151. Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas, USA.

    • Brooke L Fridley
  152. Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.

    • Robert A Vierkant
  153. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

    • Fiona Bruinsma
    •  & Graham G Giles
  154. College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA.

    • Dong Liang
  155. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Michelle A T Hildebrandt
    •  & Xifeng Wu
  156. Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Douglas A Levine
    •  & Maria Bisogna
  157. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.

    • Andrew Berchuck
  158. Department of Statistical Science, Duke University, Durham, North Carolina, USA.

    • Edwin S Iversen
  159. Cancer Control and Population Sciences, Duke Cancer Institute, Durham, North Carolina, USA.

    • Joellen M Schildkraut
  160. Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Joellen M Schildkraut
    •  & Rachel Palmieri Weber
  161. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA.

    • Patrick Concannon
  162. Genetics Institute, University of Florida, Gainesville, Florida, USA.

    • Patrick Concannon
  163. Harvard School of Public Health, Boston, Massachusetts, USA.

    • Daniel W Cramer
    •  & Kathryn L Terry
  164. Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel W Cramer
    •  & Kathryn L Terry
  165. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Elizabeth M Poole
    •  & Shelley S Tworoger
  166. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Elizabeth M Poole
    •  & Shelley S Tworoger
  167. Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.

    • Elisa V Bandera
  168. Department of Epidemiology and Biostatistics, Epidemiology Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Irene Orlow
    •  & Sara H Olson
  169. Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

    • Camilla Krakstad
    • , Helga B Salvesen
    • , Ingvild L Tangen
    •  & Line Bjorge
  170. Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.

    • Camilla Krakstad
    • , Helga B Salvesen
    • , Ingvild L Tangen
    •  & Line Bjorge
  171. Department of Gynaecology, Radboud University Medical Centre, Nijmegen, the Netherlands.

    • Anne M van Altena
    •  & Leon F A G Massuger
  172. Comprehensive Cancer Center The Netherlands, Utrecht, the Netherlands.

    • Katja K H Aben
  173. Department for Health Evidence, Radboud University Medical Centre, Nijmegen, the Netherlands.

    • Katja K H Aben
    •  & Lambertus A Kiemeney
  174. Department of Urology, Radboud University Medical Centre, Nijmegen, the Netherlands.

    • Lambertus A Kiemeney
  175. Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

    • Angela Brooks-Wilson
  176. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.

    • Angela Brooks-Wilson
  177. Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

    • Linda E Kelemen
  178. Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA.

    • Linda S Cook
  179. Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

    • Nhu D Le
  180. International Hereditary Cancer Center, Department of Genetics and Pathology, Clinic of Opthalmology, Pomeranian Medical University, Szczecin, Poland.

    • Cezary Cybulski
  181. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Hannah Yang
    • , Louise A Brinton
    • , Nicolas Wentzensen
    •  & Bu-Tian Ji
  182. Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

    • Jolanta Lissowska
  183. Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

    • Lotte Nedergaard
  184. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

    • Diana Eccles
  185. Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK.

    • Ian McNeish
  186. Cancer Research UK Clinical Trials Unit, Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK.

    • James Paul
    • , Karen Carty
    •  & Rosalind Glasspool
  187. Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, UK.

    • Nadeem Siddiqui
  188. Department of Health Research and Policy–Epidemiology, Stanford University School of Medicine, Stanford, California, USA.

    • Alice S Whittemore
    • , Joseph H Rothstein
    • , Valerie McGuire
    •  & Weiva Sieh
  189. Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Wei Zheng
    •  & Xiao-Ou Shu
  190. Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao
  191. Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Barry Rosen
  192. Department of Gynecologic-Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada.

    • Barry Rosen
  193. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.

    • Harvey A Risch
  194. Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • John R McLaughlin
  195. Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.

    • Steven A Narod
  196. Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida, USA.

    • Ann Chen
    • , Hui-Yi Lin
    •  & Zhihua Chen
  197. Department of Epidemiology, University of California–Irvine, Irvine, California, USA.

    • Argyrios Ziogas
    •  & Hoda Anton-Culver
  198. Women's Cancer, University College London Elizabeth Garrett Anderson (EGA) Institute for Women's Health, London, UK.

    • Aleksandra Gentry-Maharaj
    •  & Usha Menon
  199. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Malcolm C Pike
  200. Department of Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

    • Agnieszka Dansonka-Mieszkowska
    • , Iwona K Rzepecka
    •  & Jolanta Kupryjanczyk
  201. Department of Obstetrics, Gynecology and Oncology, 2nd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.

    • Agnieszka Timorek

Consortia

  1. EMBRACE

    A full list of members appears in the Supplementary Note.

  2. GEMO Study Collaborators

    A full list of members appears in the Supplementary Note.

  3. Breast Cancer Family Registry

    A full list of members appears in the Supplementary Note.

  4. HEBON

    A full list of members appears in the Supplementary Note.

  5. KConFab Investigators

    A full list of members appears in the Supplementary Note.

  6. Australian Cancer Study (Ovarian Cancer Investigators)

    A full list of members appears in the Supplementary Note.

  7. Australian Ovarian Cancer Study Group

    A full list of members appears in the Supplementary Note.

  8. the Consortium of Investigators of Modifiers of BRCA1 and BRCA2

    A full list of members appears in the Supplementary Note.

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Contributions

Writing group: K.B.K., A.C.A., G.C.-T., S.J.R., J. Beesley, P.P.P., S.G. Performed statistical analyses for CIMBA: K.B.K. Performed statistical analyses for OCAC: J.T. Performed the meta-analyses: K.B.K. CIMBA database management: L.M. and D.B. Supervised CIMBA statistical analyses, meta-analyses and CIMBA data management: A.C.A. Supervised OCAC statistical analyses: P.P.P. Initiated and coordinated CIMBA: G.C.-T. Coordinated OCAC: A. Berchuck and P.P.P. Conceived and coordinated the synthesis of the iCOGS array: D.F.E. Coordinated iCOGS genotyping: J.S., K. Offit, F.J.C. iCOGS genotyping, calling and quality control: J.M. Cunningham, J.D., P.S., D.F.E., K.B.K., J.T., P.P.P., A.C.A., G.C.-T. Programming support: A. Lee. Provided DNA samples and/or phenotypic data: S.J.R., J.T., A. Lee, H.C.S., K.L., S. Healey, J.M.L., T.J.S., Y.G.L., T.P., Y.B., Q.L., S.C., D.H., A. Miron, M. Southey, M.B.T., D.E.G., S.S.B., R.J., C.M.D., E.J.v.R., S.L.N., Y.C.D., T.V.O.H., L.J., A.-M.G., B.E., J.D., J. Benitez, A.O., M.J.G., I. Komenaka, J.N.W., P.G., P.P., L. Bernard, A.V., B.B., B.P., S. Manoukian, P.R., L.P., L.O., F.F., I. Konstantopoulou, J. Garber, D.F., J. Perkins, R.P., S.E., EMBRACE, A.K.G., R.K.S., A. Meindl, C.E., C.S., O.M.S., GEMO, F.D., S. Mazoyer, D.S.-L., K. Claes, K.D.L., J. Kirk, G.C.R., M. Piedmonte, D.M.O., M.d.l.H., T.C., K.A., H. Nevanlinna, J.M. Collée, M.A. Rookus, J.C.O., F.B.L.H., HEBON, E.O., O.D., I.B., J. Brunet, C.L., M.A.P., A. Jakubowska, J. Gronwald, J. Lubinski, G.S., R.B.B., M. Plante, J.S., P.S., M.M., S. Tognazzo, M.R.T., KConFab, V.S.P., X. Wang, N.L., C.I.S., N.K., J.V., C.A.A., G.P., A. Berger, C.F.S., M.-K.T., C.M.P., M.H.G., P.L.M., G.R., A.M.M., S. Tchatchou, I.L.A., G.G., A.E.T., U.B.J., T.A.K., M. Thomassen, A. Bojesen, J.Z., E.F., Y.L., M. Soller, A. Liljegren, B.A., Z.E., M.S.-A., O.I.O., R.L.N., T.R.R., K.L.N., S.M.D., K.H.L., B.Y.K., C.W., J. Lester, Australian Cancer Society, Australian Ovarian Cancer Study Group, A.H., A.B.E., M.W.B., P.A.F., D. Lambrechts, E.V.N., I.V., S. Lambrechts, E.D., J.A.D., K.G.W., M.A. Rossing, A.R., J.C.-C., S.W.-G., U.E., K.B.M., K. Odunsi, L.S., S. Lele, L.R.W., M.T.G., P.J.T., Y.B.S., I.B.R., M.D., P. Hillemanns, T.D., N.A., N.B., A. Leminen, L.M.P., R.B., F.M., J.L.K., R.P.E., R.B.N., A.d.B., F.H., I.S., P. Harter, K.M., S. Hosono, S.O., A. Jensen, S.K.K., E.H., H.N.H., M.A.N.A., S.-H.T., Y.-L.W., B.L.F., E.L.G., J.M. Cunningham, R.A.V., F.B., G.G.G., D. Liang, M.A.T.H., X. Wu, D.A.L., M.B., A. Berchuck, E.S.I., J.M.S., P.C., R.P.W., D.W.C., K.L.T., E.M.P., S.S.T., E.V.B., I.O., S.H.O., C.K., H.B.S., I.L.T., L. Bjorge, A.M.v.A., K.K.H.A., L.A.K., L.F.A.G.M., M.K., A.B.-W., L.E.K., L.S.C., N.D.L., C.C., H.Y., J. Lissowska, L.A.B., N.W., C.H., L.L., L.N., H.B., H.S., D.E., I.G.C., I.M., J. Paul, K. Carty, N.S., R.G., A.S.W., J.H.R., V.M., W.S., B.-T.J., W.Z., X.-O.S., Y.-T.G., B.R., H.A.R., J.R.M., S.A.N., A.N.M., A.C., H.-Y.L., J.P.-W., T.A.S., Y.-Y.T., Z.C., A.Z., H.A.-C., A.G.-M., U.M., P. Harrington, A.W.L., A.H.W., C.L.P., G.C., M.C.P., A.D.-M., A.T., I.K.R., J. Kupryjanczyk, M.F., H. Noushmehr, L.T., N.T., U.H., C.I., M. Tischkowitz, E.N.I., M.A.C., D.F.E., K. Offit, F.J.C., S.G., P.P.P., A.C.A., G.C.-T. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Georgia Chenevix-Trench.

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https://doi.org/10.1038/ng.3185

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