Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

Daniel R Barnes^#¹, Jonathan P Tyrer^#², Joe Dennis², Goska Leslie², Manjeet K Bolla², Michael Lush², Amber M Aeilts³, Kristiina Aittomäki⁴, Nadine Andrieu^{5

6

7

8}, Irene L Andrulis^{9

10}, Hoda Anton-Culver¹¹, Adalgeir Arason^{12

13}, Banu K Arun¹⁴, Judith Balmaña^{15

16}, Elisa V Bandera¹⁷, Rosa B Barkardottir^{12

13}, Lieke P V Berger¹⁸, Amy Berrington de Gonzalez¹⁹, Pascaline Berthet^{20

21}, Katarzyna Białkowska²², Line Bjørge^{23

24}, Amie M Blanco²⁵, Marinus J Blok²⁶, Kristie A Bobolis²⁷, Natalia V Bogdanova^{28

29

30}, James D Brenton³¹, Henriett Butz^{32

33

34}, Saundra S Buys³⁵, Maria A Caligo³⁶, Ian Campbell³⁷, Carmen Castillo³⁸, Kathleen B M Claes^{39

40

41}, Sarah V Colonna⁴², Linda S Cook⁴³, Mary B Daly⁴⁴, Agnieszka Dansonka-Mieszkowska⁴⁵, Miguel de la Hoya⁴⁶, Anna deFazio^{47

48

49

50}, Allison DePersia^{51

52}, Yuan Chun Ding⁵³, Jennifer A Doherty⁵⁴, Susan M Domchek⁵⁵, Thilo Dörk²⁹, Zakaria Einbeigi⁵⁶, Christoph Engel⁵⁷, D Gareth Evans^{58

59}, Lenka Foretova⁶⁰, Renée T Fortner^{61

62}, Florentia Fostira⁶³, Maria Cristina Foti⁶⁴, Eitan Friedman^{65

66

67}, Megan N Frone⁶⁸, Patricia A Ganz⁶⁹, Aleksandra Gentry-Maharaj^{70

71}, Gord Glendon¹⁰, Andrew K Godwin⁷², Anna González-Neira^{73

74}, Mark H Greene⁶⁸, Jacek Gronwald²², Aliana Guerrieri-Gonzaga⁷⁵, Ute Hamann⁷⁶, Thomas V O Hansen^{77

78}, Holly R Harris^{79

80}, Jan Hauke^{81

82}, Florian Heitz⁸³, Frans B L Hogervorst⁸⁴, Maartje J Hooning⁸⁵, John L Hopper⁸⁶, Chad D Huff⁸⁷, David G Huntsman^{88

89

90

91}, Evgeny N Imyanitov⁹², Louise Izatt⁹³, Anna Jakubowska^{22

94}, Paul A James^{95

96}, Ramunas Janavicius^{97

98

99}, Esther M John^{100

101

102}, Siddhartha Kar¹⁰³, Beth Y Karlan^{104

105}, Catherine J Kennedy^{47

48

49}, Lambertus A L M Kiemeney¹⁰⁶, Irene Konstantopoulou⁶³, Jolanta Kupryjanczyk⁴⁵, Yael Laitman⁶⁶, Ofer Lavie^{107

108}, Kate Lawrenson¹⁰⁹, Jenny Lester^{104

105}, Fabienne Lesueur^{5

6

7

8}, Carlos Lopez-Pleguezuelos^{110

111

112}, Phuong L Mai¹¹³, Siranoush Manoukian¹¹⁴, Taymaa May¹¹⁵, Iain A McNeish^{116

117}, Usha Menon⁷⁰, Roger L Milne^{86

118

119}, Francesmary Modugno^{120

121}, Jennifer M Mongiovi^{122

123}, Marco Montagna⁶⁴, Kirsten B Moysich¹²⁴, Susan L Neuhausen⁵³, Finn C Nielsen¹²⁵, Catherine Noguès^{126

127}, Edit Oláh³², Olufunmilayo I Olopade¹²⁸, Ana Osorio^{74

129}, Laura Papi¹³⁰, Harsh Pathak⁷², Celeste L Pearce^{131

132}, Inge S Pedersen^{133

134

135}, Ana Peixoto^{136

137}, Tanja Pejovic^{138

139}, Pei-Chen Peng¹⁴⁰, Beth N Peshkin^{141

142}, Paolo Peterlongo¹⁴³, C Bethan Powell²⁵, Darya Prokofyeva¹⁴⁴, Miquel Angel Pujana^{145

146}, Paolo Radice¹⁴⁷, Muhammad U Rashid^{76

148}, Gad Rennert^{107

149}, George Richenberg¹⁵⁰, Dale P Sandler¹⁵¹, Naoko Sasamoto^{122

152}, Veronica W Setiawan¹⁵³, Priyanka Sharma¹⁵⁴, Weiva Sieh^{87

155

156}, Christian F Singer¹⁵⁷, Katie Snape¹⁵⁸, Anna P Sokolenko⁹², Penny Soucy¹⁵⁹, Melissa C Southey^{119

160

161}, Dominique Stoppa-Lyonnet^{162

163

164}, Rebecca Sutphen¹⁶⁵, Christian Sutter¹⁶⁶, Yen Y Tan¹⁵⁷, Manuel R Teixeira^{136

137

167}, Kathryn L Terry^{123

168}, Liv Cecilie V Thomsen^{23

24

169}, Marc Tischkowitz¹⁷⁰, Amanda E Toland^{3

171}, Toon Van Gorp^{172

173}, Ana Vega^{110

111

174}, Digna R Velez Edwards¹⁷⁵, Penelope M Webb¹⁷⁶, Jeffrey N Weitzel¹⁷⁷, Nicolas Wentzensen¹⁷⁸, Alice S Whittemore^{100

179}, Stacey J Winham¹⁸⁰, Anna H Wu¹⁸¹, Siddhartha Yadav¹⁸², Yao Yu⁸⁷, Argyrios Ziogas¹¹, Andrew Berchuck¹⁸³, Fergus J Couch¹⁸⁴, Ellen L Goode¹⁸⁰, Marc T Goodman¹⁸⁵, Alvaro N Monteiro¹⁸⁶, Kenneth Offit^{187

188

189}, Susan J Ramus^{190

191}, Harvey A Risch¹⁹², Joellen M Schildkraut¹⁹³, Mads Thomassen^{194

195}, Jacques Simard^{159

196}, Douglas F Easton^{2

103}, Michelle R Jones¹⁹⁷, Georgia Chenevix-Trench¹⁹⁸, Simon A Gayther¹⁹⁷, Antonis C Antoniou², Paul D P Pharoah¹⁴⁰

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. drb54@medschl.cam.ac.uk.
² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³ Department of Internal Medicine, Division of Human Genetics, Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁴ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁵ Inserm U1331, Paris, France.
⁶ Institut Curie, Paris, France.
⁷ Mines Paris, Paris, France.
⁸ PSL Research University, Paris, France.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
¹¹ Department of Medicine, University of California Irvine, Irvine, CA, USA.
¹² Department of Pathology, Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland.
¹³ BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁴ Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵ Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁶ Department of Medical Oncology, University Hospital of Vall d'Hebron, Barcelona, Spain.
¹⁷ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹⁸ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
¹⁹ Clinical Cancer Epidemiology, Institute of Cancer Research, London, UK.
²⁰ Département de Biopathologie, Centre François Baclesse, Caen, France.
²¹ INSERM UMR1245 Cancer and Brain Genomics, Université de Rouen Normandie, Rouen, France.
²² Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
²³ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
²⁴ Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁵ Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA.
²⁶ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
²⁷ City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA.
²⁸ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³⁰ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
³¹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
³² Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
³³ National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary.
³⁴ Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary.
³⁵ Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
³⁶ SOD Genetica Molecolare, University Hospital, Pisa, Italy.
³⁷ Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
³⁸ Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
³⁹ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
⁴⁰ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
⁴¹ Cancer Research Institute Ghent, Ghent, Belgium.
⁴² Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁴³ Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO, USA.
⁴⁴ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴⁵ Department of Pathology and Laboratory Medicine, Institute of Oncology and Maria Sklodowska-Curie Cancer Center, Warsaw, Poland.
⁴⁶ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
⁴⁷ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia.
⁴⁸ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
⁴⁹ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁵⁰ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.
⁵¹ Center for Medical Genetics, Endeavor Health, Evanston, IL, USA.
⁵² The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
⁵³ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁵⁴ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁵⁵ Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
⁵⁶ Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵⁷ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵⁸ Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
⁵⁹ Genomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
⁶⁰ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
⁶¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶² Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
⁶³ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
⁶⁴ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
⁶⁵ Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
⁶⁶ The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.
⁶⁷ Assuta Medical Center, Tel-Aviv, Israel.
⁶⁸ National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA.
⁶⁹ Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA.
⁷⁰ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁷¹ Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.
⁷² Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
⁷³ Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain.
⁷⁴ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.
⁷⁵ Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
⁷⁶ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷⁷ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁷⁸ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁹ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁸⁰ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁸¹ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁸² Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁸³ Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
⁸⁴ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
⁸⁵ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁸⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
⁸⁷ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸⁸ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, BC, Canada.
⁸⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁹⁰ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁹¹ Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
⁹² Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
⁹³ Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁹⁴ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁹⁵ Parkville Familial Cancer Centre, Peter MacCallum Cancer Center and the Royal Melbourne Hospital, Melbourne, VIC, Australia.
⁹⁶ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
⁹⁷ State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
⁹⁸ Hematology, Oncology and Transfusion Medicine Center, Oncogenetics Unit, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania.
⁹⁹ Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
¹⁰⁰ Department of Epidemiology & Population Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰¹ Department of Medicine (Oncology), Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰² Stanford Cancer Institute, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁰⁴ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
¹⁰⁵ Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰⁶ Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰⁷ Technion-Israel Institute of Technology, Haifa, Israel.
¹⁰⁸ Carmel Medical Center, Haifa, Israel.
¹⁰⁹ 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.
¹¹⁰ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
¹¹¹ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
¹¹² Escola de Doutoramento Internacional, Universidade de Santiago, Santiago de Compostela, Spain.
¹¹³ Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹⁴ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹¹⁵ Princess Margaret Cancer Center, Toronto, ON, Canada.
¹¹⁶ Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK.
¹¹⁷ Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
¹¹⁸ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹¹⁹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
¹²⁰ Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
¹²¹ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹²² Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA.
¹²³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹²⁴ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹²⁵ Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹²⁶ Département d'Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France.
¹²⁷ Aix Marseille Université, INSERM, IRD, SESSTIM, Marseille, France.
¹²⁸ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
¹²⁹ Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
¹³⁰ Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy.
¹³¹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹³² Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
¹³³ Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
¹³⁴ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
¹³⁵ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
¹³⁶ Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal.
¹³⁷ Cancer Genetics Group, IPO Porto Research Center (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal.
¹³⁸ Department of Obstetrics & Gynecology, Providence Medical Center, Medford, OR, USA.
¹³⁹ Providence Cancer Center, Medford, OR, USA.
¹⁴⁰ Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁴¹ Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
¹⁴² Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, Georgetown University, Washington, DC, USA.
¹⁴³ Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Milan, Italy.
¹⁴⁴ Ufa University of Science and Technology, Ufa, Russia.
¹⁴⁵ ProCURE, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
¹⁴⁶ ProCURE, IDIBGI (Girona Biomedical Research Institute), Catalan Institute of Oncology, Girona, Spain.
¹⁴⁷ Unit of Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹⁴⁸ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
¹⁴⁹ The Association for Promotion of Research in Precision Medicine, Haifa, Israel.
¹⁵⁰ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁵¹ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹⁵² Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
¹⁵³ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁵⁴ Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA.
¹⁵⁵ Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵⁷ Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
¹⁵⁸ Deptartment of Clinical Genetics, South West Thames Centre for Genomics, St George's University Hospitals NHS Foundation Trust, London, UK.
¹⁵⁹ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹⁶⁰ Department of Clinical Pathology, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
¹⁶¹ Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, VIC, Australia.
¹⁶² Genetics Department, Institut Curie, Paris, France.
¹⁶³ INSERM U1339, Paris, France.
¹⁶⁴ Université Paris Cité, Paris, France.
¹⁶⁵ Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
¹⁶⁶ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
¹⁶⁷ Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal.
¹⁶⁸ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶⁹ Medical Birth Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
¹⁷⁰ Department of Genomic Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹⁷¹ Department of Cancer Biology and Genetics, Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
¹⁷² Division of Gynecologic Oncology, University Hospital Leuven, Leuven, Belgium.
¹⁷³ Leuven Cancer Institute, University of Leuven, Leuven, Belgium.
¹⁷⁴ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹⁷⁵ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷⁶ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QID, Australia.
¹⁷⁷ Division of Precision Prevention, The University of Kansas Cancer Center, Kansas City, KS, USA.
¹⁷⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁷⁹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸⁰ Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, MN, USA.
¹⁸¹ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁸² Department of Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁸³ Department of Gynecologic Oncology, Duke University Hospital, Durham, NC, USA.
¹⁸⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹⁸⁵ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁸⁶ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
¹⁸⁷ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸⁸ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸⁹ AnaNeo Therapeutics, New York, NY, USA.
¹⁹⁰ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW Sydney, Sydney, NSW, Australia.
¹⁹¹ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, Australia.
¹⁹² Chronic Disease Epidemiology, Yale School of Medicine, New Haven, CT, USA.
¹⁹³ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁹⁴ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
¹⁹⁵ Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁹⁶ Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
¹⁹⁷ Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁹⁸ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

^# Contributed equally.

PMID: 41266372
PMCID: PMC12635163
DOI: 10.1038/s41525-025-00529-w

Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

Daniel R Barnes et al. NPJ Genom Med. 2025.

. 2025 Nov 20;10(1):73.

doi: 10.1038/s41525-025-00529-w.

Authors

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. drb54@medschl.cam.ac.uk.
² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³ Department of Internal Medicine, Division of Human Genetics, Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁴ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁵ Inserm U1331, Paris, France.
⁶ Institut Curie, Paris, France.
⁷ Mines Paris, Paris, France.
⁸ PSL Research University, Paris, France.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
¹¹ Department of Medicine, University of California Irvine, Irvine, CA, USA.
¹² Department of Pathology, Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland.
¹³ BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁴ Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁵ Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁶ Department of Medical Oncology, University Hospital of Vall d'Hebron, Barcelona, Spain.
¹⁷ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹⁸ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
¹⁹ Clinical Cancer Epidemiology, Institute of Cancer Research, London, UK.
²⁰ Département de Biopathologie, Centre François Baclesse, Caen, France.
²¹ INSERM UMR1245 Cancer and Brain Genomics, Université de Rouen Normandie, Rouen, France.
²² Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
²³ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
²⁴ Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁵ Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA.
²⁶ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
²⁷ City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA.
²⁸ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³⁰ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
³¹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
³² Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
³³ National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary.
³⁴ Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary.
³⁵ Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
³⁶ SOD Genetica Molecolare, University Hospital, Pisa, Italy.
³⁷ Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
³⁸ Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
³⁹ Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
⁴⁰ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
⁴¹ Cancer Research Institute Ghent, Ghent, Belgium.
⁴² Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁴³ Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO, USA.
⁴⁴ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴⁵ Department of Pathology and Laboratory Medicine, Institute of Oncology and Maria Sklodowska-Curie Cancer Center, Warsaw, Poland.
⁴⁶ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
⁴⁷ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia.
⁴⁸ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
⁴⁹ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁵⁰ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.
⁵¹ Center for Medical Genetics, Endeavor Health, Evanston, IL, USA.
⁵² The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
⁵³ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁵⁴ Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁵⁵ Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
⁵⁶ Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵⁷ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵⁸ Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
⁵⁹ Genomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
⁶⁰ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
⁶¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶² Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
⁶³ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
⁶⁴ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
⁶⁵ Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
⁶⁶ The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.
⁶⁷ Assuta Medical Center, Tel-Aviv, Israel.
⁶⁸ National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA.
⁶⁹ Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA.
⁷⁰ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁷¹ Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.
⁷² Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
⁷³ Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain.
⁷⁴ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.
⁷⁵ Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
⁷⁶ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷⁷ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁷⁸ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁹ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁸⁰ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁸¹ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁸² Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁸³ Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
⁸⁴ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
⁸⁵ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁸⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
⁸⁷ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸⁸ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, BC, Canada.
⁸⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁹⁰ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁹¹ Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
⁹² Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
⁹³ Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁹⁴ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁹⁵ Parkville Familial Cancer Centre, Peter MacCallum Cancer Center and the Royal Melbourne Hospital, Melbourne, VIC, Australia.
⁹⁶ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
⁹⁷ State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
⁹⁸ Hematology, Oncology and Transfusion Medicine Center, Oncogenetics Unit, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania.
⁹⁹ Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
¹⁰⁰ Department of Epidemiology & Population Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰¹ Department of Medicine (Oncology), Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰² Stanford Cancer Institute, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁰⁴ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
¹⁰⁵ Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰⁶ Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰⁷ Technion-Israel Institute of Technology, Haifa, Israel.
¹⁰⁸ Carmel Medical Center, Haifa, Israel.
¹⁰⁹ 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.
¹¹⁰ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
¹¹¹ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
¹¹² Escola de Doutoramento Internacional, Universidade de Santiago, Santiago de Compostela, Spain.
¹¹³ Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹⁴ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹¹⁵ Princess Margaret Cancer Center, Toronto, ON, Canada.
¹¹⁶ Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK.
¹¹⁷ Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
¹¹⁸ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹¹⁹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
¹²⁰ Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
¹²¹ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹²² Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA.
¹²³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹²⁴ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹²⁵ Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹²⁶ Département d'Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France.
¹²⁷ Aix Marseille Université, INSERM, IRD, SESSTIM, Marseille, France.
¹²⁸ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
¹²⁹ Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
¹³⁰ Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy.
¹³¹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹³² Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
¹³³ Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
¹³⁴ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
¹³⁵ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
¹³⁶ Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal.
¹³⁷ Cancer Genetics Group, IPO Porto Research Center (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal.
¹³⁸ Department of Obstetrics & Gynecology, Providence Medical Center, Medford, OR, USA.
¹³⁹ Providence Cancer Center, Medford, OR, USA.
¹⁴⁰ Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁴¹ Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
¹⁴² Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, Georgetown University, Washington, DC, USA.
¹⁴³ Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Milan, Italy.
¹⁴⁴ Ufa University of Science and Technology, Ufa, Russia.
¹⁴⁵ ProCURE, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
¹⁴⁶ ProCURE, IDIBGI (Girona Biomedical Research Institute), Catalan Institute of Oncology, Girona, Spain.
¹⁴⁷ Unit of Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹⁴⁸ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
¹⁴⁹ The Association for Promotion of Research in Precision Medicine, Haifa, Israel.
¹⁵⁰ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁵¹ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹⁵² Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
¹⁵³ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁵⁴ Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA.
¹⁵⁵ Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵⁷ Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
¹⁵⁸ Deptartment of Clinical Genetics, South West Thames Centre for Genomics, St George's University Hospitals NHS Foundation Trust, London, UK.
¹⁵⁹ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹⁶⁰ Department of Clinical Pathology, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
¹⁶¹ Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, VIC, Australia.
¹⁶² Genetics Department, Institut Curie, Paris, France.
¹⁶³ INSERM U1339, Paris, France.
¹⁶⁴ Université Paris Cité, Paris, France.
¹⁶⁵ Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
¹⁶⁶ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
¹⁶⁷ Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal.
¹⁶⁸ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶⁹ Medical Birth Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
¹⁷⁰ Department of Genomic Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹⁷¹ Department of Cancer Biology and Genetics, Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
¹⁷² Division of Gynecologic Oncology, University Hospital Leuven, Leuven, Belgium.
¹⁷³ Leuven Cancer Institute, University of Leuven, Leuven, Belgium.
¹⁷⁴ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹⁷⁵ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷⁶ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QID, Australia.
¹⁷⁷ Division of Precision Prevention, The University of Kansas Cancer Center, Kansas City, KS, USA.
¹⁷⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁷⁹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸⁰ Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, MN, USA.
¹⁸¹ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁸² Department of Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁸³ Department of Gynecologic Oncology, Duke University Hospital, Durham, NC, USA.
¹⁸⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹⁸⁵ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁸⁶ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
¹⁸⁷ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸⁸ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸⁹ AnaNeo Therapeutics, New York, NY, USA.
¹⁹⁰ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW Sydney, Sydney, NSW, Australia.
¹⁹¹ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, Australia.
¹⁹² Chronic Disease Epidemiology, Yale School of Medicine, New Haven, CT, USA.
¹⁹³ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁹⁴ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
¹⁹⁵ Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁹⁶ Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
¹⁹⁷ Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁹⁸ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

^# Contributed equally.

PMID: 41266372
PMCID: PMC12635163
DOI: 10.1038/s41525-025-00529-w

Abstract

Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3'-UTR SNP rs78378222-T's association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28-1.62, P = 1.76 × 10^-9). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37-1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date - demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.

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Conflict of interest statement

Competing interests: L.B. has received honoraria for lectures from GlaxoSmithKline, Merck Sharp and Dohme, has received a research grant from AstraZeneca for a researcher-initiated trial, and has had leadership roles in Onkologisk Forum between 2018 and 2022 and in the Nordic Society of Gynaecological Oncology (NSGO) and NSGO-Clinical Trial Unit since 2021. She is faculty member the Gynaecological Cancers group, European Society of Medical Oncology (ESMO) external expert in gynecologic oncology for the Norwegian National Expert Panel for Persons with Serious Life-Shortening Diseases and Member of the national specialist group in oncology, Sykehusinnkjøp HF as well as board member for KinN Therapeutics Bergen - a biopharmaceutical company focused on tailored preclinical oncology services for the development of novel anticancer compounds. A.d. has received research support from AstraZeneca and Illumina, and speakers fee from AstraZeneca. A.G.-M. has received research funding for my role, has been funded by grants from the Medical Research Council (MRC), Cancer Research UK (CRUK), National Institute for Health Research (NIHR) and The Eve Appeal, has funded research collaborations with industry - iLOF (intelligent Lab on Fiber), RNA Guardian, Micronoma and Mercy BioAnalytics, has research collaborations with academic institutions: University of Cambridge, QIMR Berghofer Medical Research Institute, Imperial College London, University of Innsbruck and Dana Farber USA, is a Co-Director Research Domain Trials, and has consultancy arrangement with Mercy BioAnalytics. F.H. has received personal fees and is on advisory boards of NovoCure, PharmaMar, AstraZeneca, Roche, Tesaro, GSK, Zailabs, Abbvie, MSD. A.E.T. has received grant funding through the National Institutes of Health and has study section membership for the National Institutes of Health. P.M.W. has received grant funding from AstraZeneca (06/2017-03/2021) for an unrelated study of ovarian cancer. D.F.E. and A.C.A. are listed as creators of the BOADICEA model which has been licensed by Cambridge Enterprise (University of Cambridge) for commercial purposes.

Figures

**Fig. 1. Manhattan plot showing the associations with HGSOC from the meta-analysis of OCAC, UKBB and CIMBA summary association data.**
The dashed line is the genome-wide statistical significance level (P = 5 × 10⁻⁸). The eight independent genome-wide statistically significant variants at seven novel loci are shown as red triangles.

**Fig. 2. Predicted cumulative risks of developing EOC by PGS percentiles.**
Predicted cumulative risks of developing EOC based on the PGS₆₄₅₁₈ at various percentiles of the PGS distribution for: a the general population (0.7% for 1^st percentile to 3.9% for the 99^th percentile), b *BRCA1* PV carriers (20.7% for 1^st percentile to 74.1% for the 99^th percentile), and c *BRCA2* PV carriers (7.3% for 1^st percentile to 35.7% for the 99^th percentile).

**Fig. 3**
Schema describing the analytical process for the GWAS analyses from OCAC, UKBB and CIMBA, and subsequent meta-analyses.

Fig. 4. Schema describing the development of polygenic models, determining the optimal model, and validating the resultant polygenic score in European ancestry women from UKBB and East Asian ancestry women from BBJ.
S4 select and shrink using summary statistics, PGM polygenic model, NMOC non-mucinous ovarian cancer, LD linkage disequilibrium.

See this image and copyright information in PMC

Update of

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.
Barnes DR, Tyrer JP, Dennis J, Leslie G, Bolla MK, Lush M, Aeilts AM, Aittomäki K, Andrieu N, Andrulis IL, Anton-Culver H, Arason A, Arun BK, Balmaña J, Bandera EV, Barkardottir RB, Berger LPV, de Gonzalez AB, Berthet P, Białkowska K, Bjørge L, Blanco AM, Blok MJ, Bobolis KA, Bogdanova NV, Brenton JD, Butz H, Buys SS, Caligo MA, Campbell I, Castillo C, Claes KBM; GEMO Study Collaborators; EMBRACE Collaborators; Colonna SV, Cook LS, Daly MB, Dansonka-Mieszkowska A, de la Hoya M, deFazio A, DePersia A, Ding YC, Domchek SM, Dörk T, Einbeigi Z, Engel C, Evans DG, Foretova L, Fortner RT, Fostira F, Foti MC, Friedman E, Frone MN, Ganz PA, Gentry-Maharaj A, Glendon G, Godwin AK, González-Neira A, Greene MH, Gronwald J, Guerrieri-Gonzaga A, Hamann U, Hansen TVO, Harris HR, Hauke J, Heitz F, Hogervorst FBL, Hooning MJ, Hopper JL, Huff CD, Huntsman DG, Imyanitov EN; kConFab Investigators; Izatt L, Jakubowska A, James PA, Janavicius R, John EM, Kar S, Karlan BY, Kennedy CJ, Kiemeney LALM, Konstantopoulou I, Kupryjanczyk J, Laitman Y, Lavie O, Lawrenson K, Lester J, Lesueur F, Lopez-Pleguezuelos C, Mai PL, Manoukian S, May T, McNeish IA, Menon U, Milne RL, Modugno F, Mongiovi JM, Montagna M, … See abstract for full author list ➔ Barnes DR, et al. medRxiv [Preprint]. 2024 Mar 4:2024.02.29.24303243. doi: 10.1101/2024.02.29.24303243. medRxiv. 2024. Update in: NPJ Genom Med. 2025 Nov 20;10(1):73. doi: 10.1038/s41525-025-00529-w. PMID: 38496424 Free PMC article. Updated. Preprint.

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Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

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Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer

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Update of

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