This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2024 Mar 4:2024.02.29.24303243.

doi: 10.1101/2024.02.29.24303243.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

Daniel R Barnes¹, Jonathan P Tyrer¹, Joe Dennis¹, Goska Leslie¹, Manjeet K Bolla¹, Michael Lush¹, Amber M Aeilts², Kristiina Aittomäki³, Nadine Andrieu^{4

5

6

7}, Irene L Andrulis^{8

9}, Hoda Anton-Culver¹⁰, Adalgeir Arason^{11

12}, Banu K Arun¹³, Judith Balmaña^{14

15}, Elisa V Bandera¹⁶, Rosa B Barkardottir^{11

12}, Lieke P V Berger¹⁷, Amy Berrington de Gonzalez¹⁸, Pascaline Berthet¹⁹, Katarzyna Białkowska²⁰, Line Bjørge^{21

22}, Amie M Blanco²³, Marinus J Blok²⁴, Kristie A Bobolis²⁵, Natalia V Bogdanova^{26

27

28}, James D Brenton²⁹, Henriett Butz^{30

31

32}, Saundra S Buys³³, Maria A Caligo³⁴, Ian Campbell³⁵, Carmen Castillo³⁶, Kathleen B M Claes^{37

38

39}; GEMO Study Collaborators; EMBRACE Collaborators; Sarah V Colonna⁴⁰, Linda S Cook⁴¹, Mary B Daly⁴², Agnieszka Dansonka-Mieszkowska⁴³, Miguel de la Hoya⁴⁴, Anna deFazio^{45

46

47

48}, Allison DePersia^{49

50}, Yuan Chun Ding⁵¹, Susan M Domchek⁵², Thilo Dörk²⁷, Zakaria Einbeigi⁵³, Christoph Engel⁵⁴, D Gareth Evans^{55

56}, Lenka Foretova⁵⁷, Renée T Fortner^{58

59}, Florentia Fostira⁶⁰, Maria Cristina Foti⁶¹, Eitan Friedman^{62

63

64}, Megan N Frone⁶⁵, Patricia A Ganz⁶⁶, Aleksandra Gentry-Maharaj⁶⁷, Gord Glendon⁹, Andrew K Godwin⁶⁸, Anna González-Neira^{69

70}, Mark H Greene⁶⁵, Jacek Gronwald²⁰, Aliana Guerrieri-Gonzaga⁷¹, Ute Hamann⁷², Thomas V O Hansen^{73

74}, Holly R Harris^{75

76}, Jan Hauke^{77

78}, Florian Heitz⁷⁹, Frans B L Hogervorst⁸⁰, Maartje J Hooning⁸¹, John L Hopper⁸², Chad D Huff⁸³, David G Huntsman^{84

85

86

87}, Evgeny N Imyanitov⁸⁸; kConFab Investigators; Louise Izatt⁸⁹, Anna Jakubowska^{20

90}, Paul A James^{91

92}, Ramunas Janavicius^{93

94

95}, Esther M John^{96

97

98}, Siddhartha Kar⁹⁹, Beth Y Karlan^{100

101}, Catherine J Kennedy^{45

46

47}, Lambertus A L M Kiemeney¹⁰², Irene Konstantopoulou⁶⁰, Jolanta Kupryjanczyk⁴³, Yael Laitman⁶³, Ofer Lavie^{103

104}, Kate Lawrenson¹⁰⁵, Jenny Lester^{100

101}, Fabienne Lesueur^{4

5

6

7}, Carlos Lopez-Pleguezuelos^{106

107

108}, Phuong L Mai¹⁰⁹, Siranoush Manoukian¹¹⁰, Taymaa May¹¹¹, Iain A McNeish^{112

113}, Usha Menon⁶⁷, Roger L Milne^{82

114

115}, Francesmary Modugno^{116

117}, Jennifer M Mongiovi^{118

119}, Marco Montagna¹²⁰, Kirsten B Moysich¹²¹, Susan L Neuhausen⁵¹, Finn C Nielsen¹²², Catherine Noguès^{123

124}, Edit Oláh³⁰, Olufunmilayo I Olopade¹²⁵, Ana Osorio^{70

126}, Laura Papi¹²⁷, Harsh Pathak⁶⁸, Celeste L Pearce^{128

129}, Inge S Pedersen^{130

131

132}, Ana Peixoto^{133

134}, Tanja Pejovic^{135

136}, Pei-Chen Peng¹³⁷, Beth N Peshkin^{138

139}, Paolo Peterlongo¹⁴⁰, C Bethan Powell¹⁴¹, Darya Prokofyeva¹⁴², Miquel Angel Pujana^{143

144}, Paolo Radice¹⁴⁵, Muhammad U Rashid^{72

146}, Gad Rennert^{103

147}, George Richenberg¹⁴⁸, Dale P Sandler¹⁴⁹, Naoko Sasamoto^{118

150}, Veronica W Setiawan¹⁵¹, Priyanka Sharma¹⁵², Weiva Sieh^{83

153

154}, Christian F Singer¹⁵⁵, Katie Snape¹⁵⁶, Anna P Sokolenko⁸⁸, Penny Soucy¹⁵⁷, Melissa C Southey^{115

158

159}, Dominique Stoppa-Lyonnet^{160

161

162}, Rebecca Sutphen¹⁶³, Christian Sutter¹⁶⁴, Manuel R Teixeira^{133

134

165}, Kathryn L Terry^{119

166}, Liv Cecilie V Thomsen^{21

22

167}, Marc Tischkowitz^{168

169}, Amanda E Toland^{2

170}, Toon Van Gorp^{171

172}, Ana Vega^{106

107

173}, Digna R Velez Edwards¹⁷⁴, Penelope M Webb¹⁷⁵, Jeffrey N Weitzel¹⁷⁶, Nicolas Wentzensen¹⁷⁷, Alice S Whittemore^{96

178}, Stacey J Winham¹⁷⁹, Anna H Wu¹⁸⁰, Siddhartha Yadav¹⁸¹, Yao Yu⁸³, Argyrios Ziogas¹⁰, Andrew Berchuck¹⁸², Fergus J Couch¹⁸³, Ellen L Goode¹⁷⁹, Marc T Goodman¹⁸⁴, Alvaro N Monteiro¹⁸⁵, Kenneth Offit^{186

187

188}, Susan J Ramus^{189

190}, Harvey A Risch¹⁹¹, Joellen M Schildkraut¹⁹², Mads Thomassen^{193

194}, Jacques Simard^{157

195}, Douglas F Easton^{1

99}, Michelle R Jones¹⁹⁶, Georgia Chenevix-Trench¹⁹⁷, Simon A Gayther¹⁹⁶, Antonis C Antoniou¹, Paul D P Pharoah¹³⁷

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² Department of Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH, USA.
³ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁴ Inserm U900, Paris, France.
⁵ Institut Curie, Paris, France.
⁶ Mines ParisTech, Fontainebleau, France.
⁷ PSL Research University, Paris, France.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.
¹⁰ Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹¹ Department of Pathology, Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland.
¹² BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹³ Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁵ Department of Medical Oncology, University Hospital of Vall d'Hebron, Barcelona, Spain.
¹⁶ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹⁷ University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands.
¹⁸ Clinical Cancer Epidemiology, Institute of Cancer Research, London, UK.
¹⁹ Département de Biopathologie, Centre François Baclesse, Caen, France.
²⁰ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
²¹ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
²² Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
²³ Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA.
²⁴ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
²⁵ City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA.
²⁶ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁷ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²⁸ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
²⁹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
³⁰ Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
³¹ National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary.
³² Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary.
³³ Department of Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, USA.
³⁴ SOD Genetica Molecolare, University Hospital, Pisa, Italy.
³⁵ Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
³⁶ Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
³⁷ Centre for Medical Genetics, Ghent University, Gent, Belgium.
³⁸ Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium.
³⁹ Cancer Research Institute Ghent, Ghent, Belgium.
⁴⁰ Department of Internal Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, USA.
⁴¹ Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO, USA.
⁴² Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴³ Department of Pathology and Laboratory Medicine, Institute of Oncology and Maria Sklodowska-Curie Cancer Center, Warsaw, Poland.
⁴⁴ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
⁴⁵ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.
⁴⁶ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
⁴⁷ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁴⁸ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia.
⁴⁹ Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
⁵⁰ The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
⁵¹ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁵² Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
⁵³ Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵⁴ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵⁵ 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.
⁵⁶ Genomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
⁵⁷ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
⁵⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵⁹ Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
⁶⁰ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
⁶¹ Veneto Institute of Oncology IOV-IRCSS, Italy.
⁶² Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
⁶³ The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.
⁶⁴ Assuta Medical Center, Tel-Aviv, Israel.
⁶⁵ National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA.
⁶⁶ Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA.
⁶⁷ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁶⁸ Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
⁶⁹ Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain.
⁷⁰ Spanish Network on Rare Diseases, Madrid, Spain.
⁷¹ Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
⁷² Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷³ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁷⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁵ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁷⁶ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁷⁷ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁸ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁹ Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
⁸⁰ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
⁸¹ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁸² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
⁸³ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸⁴ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, BC, Canada.
⁸⁵ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁸⁶ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁸⁷ Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
⁸⁸ Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
⁸⁹ Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁹⁰ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁹¹ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
⁹² Parkville Familial Cancer Centre, Peter MacCallum Cancer Center and the Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁹³ State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
⁹⁴ Hematology, Oncology and Transfusion Medicine Center, Oncogenetics Unit, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania.
⁹⁵ Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
⁹⁶ Department of Epidemiology & Population Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
⁹⁷ Department of Medicine (Oncology), Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
⁹⁸ Stanford Cancer Institute, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
⁹⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁰⁰ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
¹⁰¹ Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰² Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰³ Technion-Israel Institute of Technology, Haifa, Israel.
¹⁰⁴ Carmel Medical Center, Haifa, Israel.
¹⁰⁵ 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.
¹⁰⁶ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
¹⁰⁷ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
¹⁰⁸ Escola de Doutoramento Internacional, Universidade de Santiago, Santiago de Compostela, Spain.
¹⁰⁹ Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹⁰ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹¹¹ Princess Margaret Cancer Center, Toronto, Canada.
¹¹² Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK.
¹¹³ Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
¹¹⁴ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
¹¹⁵ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
¹¹⁶ Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
¹¹⁷ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹⁸ Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA.
¹¹⁹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹²⁰ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
¹²¹ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹²² Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹²³ Département d'Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France.
¹²⁴ Aix Marseille Université, INSERM, IRD, SESSTIM, Marseille, France.
¹²⁵ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
¹²⁶ Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Madrid, Spain.
¹²⁷ Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy.
¹²⁸ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹²⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
¹³⁰ Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
¹³¹ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
¹³² Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
¹³³ Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal.
¹³⁴ 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.
¹³⁵ Department of Obstetrics & Gynecology, Providence Medical Center, Medford, OR, USA.
¹³⁶ Providence Cancer Center, Medford, OR, USA.
¹³⁷ Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³⁸ Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
¹³⁹ Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, Georgetown University, Washington, DC, USA.
¹⁴⁰ Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
¹⁴¹ Hereditary Cancer Program, Kaiser Permanente Northern California, San Francisco, CA, USA.
¹⁴² Ufa University of Science and Technology, Ufa, Russia.
¹⁴³ ProCURE, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
¹⁴⁴ ProCURE, IDIBGI (Girona Biomedical Research Institute), Catalan Institute of Oncology, Girona, Spain.
¹⁴⁵ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹⁴⁶ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
¹⁴⁷ The Association for Promotion of Research in Precision Medicine, Haifa, Israel.
¹⁴⁸ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁴⁹ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Rockville, MD, USA.
¹⁵⁰ Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
¹⁵¹ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁵² Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA.
¹⁵³ Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵⁵ Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
¹⁵⁶ Medical Genetics Unit, St George's, University of London, London, UK.
¹⁵⁷ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹⁵⁸ Department of Clinical Pathology, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
¹⁵⁹ Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, Victoria, Australia.
¹⁶⁰ Genetics Department, Institut Curie, Paris, France.
¹⁶¹ Unité INSERM U830, Paris, France.
¹⁶² Université Paris Cité, Paris, France.
¹⁶³ Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
¹⁶⁴ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
¹⁶⁵ Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal.
¹⁶⁶ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶⁷ Medical Birth Registry of Norway, Norwegian Institute of Public Health, Norway.
¹⁶⁸ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
¹⁶⁹ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹⁷⁰ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
¹⁷¹ Division of Gynecologic Oncology, University Hospital Leuven, Leuven, Belgium.
¹⁷² Leuven Cancer Institute, University of Leuven, Leuven, Belgium.
¹⁷³ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹⁷⁴ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷⁵ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹⁷⁶ Clinical Cancer Genomics, City of Hope, Duarte, CA, USA.
¹⁷⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁷⁸ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷⁹ Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, MN, USA.
¹⁸⁰ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁸¹ Department of Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁸² Department of Gynecologic Oncology, Duke University Hospital, Durham, NC, USA.
¹⁸³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹⁸⁴ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁸⁵ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
¹⁸⁶ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸⁸ AnaNeo Therapeutics, New York, NY, USA.
¹⁸⁹ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
¹⁹⁰ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
¹⁹¹ Chronic Disease Epidemiology, Yale School of Medicine, New Haven, CT, USA.
¹⁹² Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁹³ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
¹⁹⁴ Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁹⁵ Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
¹⁹⁶ Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁹⁷ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

PMID: 38496424
PMCID: PMC10942532
DOI: 10.1101/2024.02.29.24303243

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

Daniel R Barnes et al. medRxiv. 2024.

[Preprint]. 2024 Mar 4:2024.02.29.24303243.

doi: 10.1101/2024.02.29.24303243.

Authors

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² Department of Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH, USA.
³ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁴ Inserm U900, Paris, France.
⁵ Institut Curie, Paris, France.
⁶ Mines ParisTech, Fontainebleau, France.
⁷ PSL Research University, Paris, France.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.
¹⁰ Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹¹ Department of Pathology, Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland.
¹² BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹³ Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁵ Department of Medical Oncology, University Hospital of Vall d'Hebron, Barcelona, Spain.
¹⁶ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹⁷ University Medical Center Groningen, Department of Genetics, University of Groningen, Groningen, The Netherlands.
¹⁸ Clinical Cancer Epidemiology, Institute of Cancer Research, London, UK.
¹⁹ Département de Biopathologie, Centre François Baclesse, Caen, France.
²⁰ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
²¹ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
²² Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
²³ Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA.
²⁴ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
²⁵ City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA.
²⁶ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁷ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²⁸ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
²⁹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
³⁰ Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
³¹ National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary.
³² Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary.
³³ Department of Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, USA.
³⁴ SOD Genetica Molecolare, University Hospital, Pisa, Italy.
³⁵ Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
³⁶ Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
³⁷ Centre for Medical Genetics, Ghent University, Gent, Belgium.
³⁸ Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium.
³⁹ Cancer Research Institute Ghent, Ghent, Belgium.
⁴⁰ Department of Internal Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, USA.
⁴¹ Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO, USA.
⁴² Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴³ Department of Pathology and Laboratory Medicine, Institute of Oncology and Maria Sklodowska-Curie Cancer Center, Warsaw, Poland.
⁴⁴ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
⁴⁵ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.
⁴⁶ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
⁴⁷ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁴⁸ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia.
⁴⁹ Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
⁵⁰ The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
⁵¹ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁵² Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
⁵³ Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁵⁴ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵⁵ 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.
⁵⁶ Genomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
⁵⁷ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
⁵⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵⁹ Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
⁶⁰ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
⁶¹ Veneto Institute of Oncology IOV-IRCSS, Italy.
⁶² Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
⁶³ The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.
⁶⁴ Assuta Medical Center, Tel-Aviv, Israel.
⁶⁵ National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA.
⁶⁶ Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA.
⁶⁷ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁶⁸ Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
⁶⁹ Human Genotyping Unit-CeGen, Spanish National Cancer Research Centre, Madrid, Spain.
⁷⁰ Spanish Network on Rare Diseases, Madrid, Spain.
⁷¹ Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
⁷² Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷³ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁷⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁵ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁷⁶ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁷⁷ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁸ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁹ Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
⁸⁰ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
⁸¹ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁸² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
⁸³ Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸⁴ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, BC, Canada.
⁸⁵ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁸⁶ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
⁸⁷ Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
⁸⁸ Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
⁸⁹ Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁹⁰ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁹¹ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
⁹² Parkville Familial Cancer Centre, Peter MacCallum Cancer Center and the Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁹³ State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
⁹⁴ Hematology, Oncology and Transfusion Medicine Center, Oncogenetics Unit, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania.
⁹⁵ Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
⁹⁶ Department of Epidemiology & Population Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
⁹⁷ Department of Medicine (Oncology), Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
⁹⁸ Stanford Cancer Institute, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
⁹⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁰⁰ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
¹⁰¹ Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁰² Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰³ Technion-Israel Institute of Technology, Haifa, Israel.
¹⁰⁴ Carmel Medical Center, Haifa, Israel.
¹⁰⁵ 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.
¹⁰⁶ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
¹⁰⁷ Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
¹⁰⁸ Escola de Doutoramento Internacional, Universidade de Santiago, Santiago de Compostela, Spain.
¹⁰⁹ Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹⁰ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹¹¹ Princess Margaret Cancer Center, Toronto, Canada.
¹¹² Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK.
¹¹³ Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
¹¹⁴ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
¹¹⁵ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
¹¹⁶ Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA.
¹¹⁷ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹⁸ Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA.
¹¹⁹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹²⁰ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
¹²¹ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
¹²² Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹²³ Département d'Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France.
¹²⁴ Aix Marseille Université, INSERM, IRD, SESSTIM, Marseille, France.
¹²⁵ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
¹²⁶ Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Madrid, Spain.
¹²⁷ Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy.
¹²⁸ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹²⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
¹³⁰ Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
¹³¹ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
¹³² Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
¹³³ Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal.
¹³⁴ 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.
¹³⁵ Department of Obstetrics & Gynecology, Providence Medical Center, Medford, OR, USA.
¹³⁶ Providence Cancer Center, Medford, OR, USA.
¹³⁷ Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³⁸ Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
¹³⁹ Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, Georgetown University, Washington, DC, USA.
¹⁴⁰ Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
¹⁴¹ Hereditary Cancer Program, Kaiser Permanente Northern California, San Francisco, CA, USA.
¹⁴² Ufa University of Science and Technology, Ufa, Russia.
¹⁴³ ProCURE, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
¹⁴⁴ ProCURE, IDIBGI (Girona Biomedical Research Institute), Catalan Institute of Oncology, Girona, Spain.
¹⁴⁵ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹⁴⁶ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
¹⁴⁷ The Association for Promotion of Research in Precision Medicine, Haifa, Israel.
¹⁴⁸ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁴⁹ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Rockville, MD, USA.
¹⁵⁰ Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA.
¹⁵¹ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁵² Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA.
¹⁵³ Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵⁵ Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
¹⁵⁶ Medical Genetics Unit, St George's, University of London, London, UK.
¹⁵⁷ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹⁵⁸ Department of Clinical Pathology, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
¹⁵⁹ Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, Victoria, Australia.
¹⁶⁰ Genetics Department, Institut Curie, Paris, France.
¹⁶¹ Unité INSERM U830, Paris, France.
¹⁶² Université Paris Cité, Paris, France.
¹⁶³ Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
¹⁶⁴ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
¹⁶⁵ Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal.
¹⁶⁶ Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶⁷ Medical Birth Registry of Norway, Norwegian Institute of Public Health, Norway.
¹⁶⁸ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
¹⁶⁹ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹⁷⁰ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
¹⁷¹ Division of Gynecologic Oncology, University Hospital Leuven, Leuven, Belgium.
¹⁷² Leuven Cancer Institute, University of Leuven, Leuven, Belgium.
¹⁷³ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹⁷⁴ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷⁵ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹⁷⁶ Clinical Cancer Genomics, City of Hope, Duarte, CA, USA.
¹⁷⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁷⁸ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷⁹ Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, MN, USA.
¹⁸⁰ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
¹⁸¹ Department of Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁸² Department of Gynecologic Oncology, Duke University Hospital, Durham, NC, USA.
¹⁸³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹⁸⁴ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁸⁵ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
¹⁸⁶ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
¹⁸⁸ AnaNeo Therapeutics, New York, NY, USA.
¹⁸⁹ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
¹⁹⁰ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
¹⁹¹ Chronic Disease Epidemiology, Yale School of Medicine, New Haven, CT, USA.
¹⁹² Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁹³ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
¹⁹⁴ Clinical Genome Center, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹⁹⁵ Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
¹⁹⁶ Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁹⁷ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

PMID: 38496424
PMCID: PMC10942532
DOI: 10.1101/2024.02.29.24303243

Abstract

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).

Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan.

Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10^-9). 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 in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62).

Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

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Figures

**Figure 1:**
Schema describing the analytical process for the GWAS analyses from OCAC, UKBB and CIMBA, and subsequent meta-analyses.

**Figure 2:**
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.

**Figure 3:**
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.

**Figure 4:**
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).

See this image and copyright information in PMC

References

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This is a preprint.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

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Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

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