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

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<sup>-9</sup>). 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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npj Genomic Medicine
Published
2025-11-20
DOI
https://doi.org/10.1038/s41525-025-00529-w
Primary Topic
BRCA gene mutations in cancer
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article
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article

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

George Richenberg, Kristie Bobolis, Celeste Leigh Pearce, Maria A. Caligo et al.
npj Genomic Medicine
BRCA gene mutations in cancer
article

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

George Richenberg, Kristie Bobolis, Celeste Leigh Pearce, Maria A. Caligo, Megan N. Frone, Beth N. Peshkin, Weiva Sieh, Harvey A. Risch, Elisa V. Bandera, C. Bethan Powell, Michael Lush, Jonathan P. Tyrer, Ellen L. Goode, Natalia Bogdanova, Paul A. James, Banu Arun, Harsh B. Pathak, Penelope M. Webb, Miguel Ángel Pujana, Amie Blanco, Line Bjørge, Inge Søkilde Pedersen, Florian Heitz, Goska Leslie, Ofer Lavie, Anna DeFazio, Thilo Dörk, Liv Cecilie Vestrheim Thomsen, Thomas van Overeem Hansen, Stacey J. Winham, Анна Петровна Соколенко, Kathleen Claes, Ana Vega, Linda Cook, Jeffrey N. Weitzel, Maria Cristina Foti, Joe Dennis, Zakaria Einbeigi, Veronica Wendy Setiawan, Eitan Friedman, Michelle R. Jones, Christoph Engel, David Huntsman, Andrew K. Godwin, Siranoush Manoukian, Agnieszka Dansonka‐Mieszkowska, Marinus J. Blok, Ian Campbell, Marc T. Goodman, Antonis C. Antoniou, Anna González‐Neira, Louise Izatt, Ana Osório, Yen Y. Tan, Georgia Chenevix‐Trench, Roger Laughlin Milne, Muhammad Usman Rashid, Laura Papi, Lenka Foretová, Lieke P. V. Berger, Marco Montagna, Digna R. Velez Edwards, Lambertus A.L.M. Kiemeney, Penny Soucy, Simon A. Gayther, Manuel R. Teixeira, Henriett Butz, Amanda Ewart Toland, Douglas F. Easton, Priyanka Sharma, Aðalgeir Arason, Esther M. John, Catherine J. Kennedy, Miguel de la Hoya, Susan J. Ramus, Irene L. Andrulis, Yuan Chun Ding, James D. Brenton, Katarzyna Białkowska, Amber M. Aeilts, Irene Konstantopoulou, Marc Tischkowitz, Daniel R. Barnes, Amy Berrington de González, Anna Jakubowska, Olufunmilayo I. Olopade, Sarah V. Colonna, Dale P. Sandler, Jacques Simard, Renée T. Fortner, Susan L. Neuhausen, Christian Sutter, Aliana Guerrieri‐Gonzaga, Holly Ruth Harris, Carmen J. Contreras‐Castillo, Tanja Pejović, Álvaro N.A. Monteiro, Jan Hauke, Argyrios Ziogas, Rósa B. Barkardóttir, Maartje J. Hooning, Kate Lawrenson, Darya Prokofyeva, Siddhartha Kar, Jennifer A. Doherty, Jolanta Kupryjańczyk, Naoko Sasamoto, Hoda Anton‐Culver, Siddhartha Yadav, Jennifer M. Mongiovi, Toon Van Gorp, Usha Menon, Fabienne Lesueur, Gad Rennert, Beth Y. Karlan, Allison DePersia, Yao Yu, Judith Balmañà, Pei-Chen Peng, Katie M.G. Snape, Ana Peixoto, D. Gareth Evans, Paul D.P. Pharoah, Mark H. Greene, Iain A. McNeish, Nadine Andrieu, Melissa C. Southey, Carlos Lopez-Pleguezuelos, Patricia A. Ganz, Saundra S. Buys, Kathryn L. Terry, Anna H. Wu, Joellen M. Schildkraut, Pascaline Berthet, Ute Hamann, Francesmary Modugno, D Stoppa-Lyonnet, Aleksandra Gentry-Maharaj, Jenny Lester, Paolo Peterlongo, Paolo Radice, Andrew Berchuck, Jacek Gronwald, John L. Hopper, Yael Laitman, Kristiina Aittomäki, Mads Thomassen, L. Phuong, Mary B. Daly, Rebecca Sutphen, Taymaa May, Kenneth Offit, Susan M. Domchek, Kirsten B. Moysich, Gord Glendon, Christian F. Singer, Finn C. Nielsen, Alice S. Whittemore, Catherine Noguès, Florentia Fostira, Edith Oláh, Fergus J. Couch, Manjeet K. Bolla, Chad Huff, Nicolas Wentzensen, Evgeny N. Imyanitov, Ramunas Janavicius
article en

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<sup>-9</sup>). 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.

npj Genomic MedicineVol. 10(1)
Rutgers, The State University of New Jersey (US), University of Southern California (US), University of Copenhagen (DK), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), Fox Chase Cancer Center (US), BC Cancer Agency (CA), Roswell Park Comprehensive Cancer Center (US), The University of Sydney (AU), Mayo Clinic (US), Norwegian Institute of Public Health (NO), University Medical Center Groningen (NL), Memorial Sloan Kettering Cancer Center (US), University of Helsinki (FI), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), University of British Columbia (CA), Institute of Cancer Research (GB), Radboud University Nijmegen (NL), Colorado School of Public Health (US), Inserm (FR), University of California, Los Angeles (US), Tel Aviv University (IL), University of Iceland (IS), The University of Melbourne (AU), University of Groningen (NL), University of Pittsburgh (US), Vilnius University (LT), Technion – Israel Institute of Technology (IL), University of Southern Denmark (DK), German Cancer Research Center (DE), University of California, San Francisco (US), University of Cologne (DE), Universidade do Porto (PT), Georgetown University (US), University of Toronto (CA), Cancer Council Victoria (AU), Guy's and St Thomas' NHS Foundation Trust (GB), Universidade de Santiago de Compostela (ES), University of Washington (US), National Centre of Scientific Research "Demokritos" (GR), University of California, Irvine (US), Université Paris Cité (FR), Lunenfeld-Tanenbaum Research Institute (CA), Aix-Marseille Université (FR), QIMR Berghofer Medical Research Institute (AU), University of Utah (US), Heidelberg University (DE), University of Cambridge (GB), University of South Florida (US), Université Paris Sciences et Lettres (FR), University of Michigan (US), Manchester Academic Health Science Centre (GB), Sheba Medical Center (IL), Georgetown University Medical Center (US), Aalborg University Hospital (DK), Helsinki University Hospital (FI), Peter MacCallum Cancer Centre (AU), Assuta Medical Center (IL), Haukeland University Hospital (NO), Huntsman Cancer Institute (US), St George’s University Hospitals NHS Foundation Trust (GB), Ghent University Hospital (BE), Cancer Research UK (GB), Odense University Hospital (DK), Cancer Institute of New South Wales (AU), University Hospital Heidelberg (DE), Copenhagen University Hospital (DK), Princess Margaret Cancer Centre (CA), Rigshospitalet (DK), Vancouver General Hospital (CA), Radboud University Medical Center (NL), Westmead Hospital (AU), University of Manchester (GB), The Netherlands Cancer Institute (NL), Moffitt Cancer Center (US), Ghent University (BE), Yale University (US), Maastricht University (NL), Medizinische Hochschule Hannover (DE), National Institute for Health and Care Research (GB), University of Bristol (GB), University of Chicago (US), Institut d'Investigació Biomédica de Bellvitge (ES), Fred Hutch Cancer Center (US), Spanish National Cancer Research Centre (ES), MRC Clinical Trials Unit at UCL (GB), Comprehensive Cancer Center Vienna (AT), Centre hospitalier universitaire de Québec (CA), National Institute of Environmental Health Sciences (US), Ovarian Cancer Action (GB), Complejo Hospitalario Universitario de Santiago (ES), Magee-Womens Research Institute (US), The University of Kansas Cancer Center (US), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (ES), State Research Institute Centre for Innovative Medicine (LT), Instituto Português de Oncologia Francisco Gentil (PT), Ufa Institute of Chemistry (RU), Normandie Université (FR), Magee-Womens Hospital (US), National University Hospital of Iceland (IS), St Mary's Hospital (GB), Institut Català d'Oncologia (ES), Istituto Oncologico Veneto (IT), City of Hope (US), IPO Porto (PT), Centre for Biomedical Network Research on Rare Diseases (ES), Institut d'Investigació Biomèdica de Girona (ES), Carmel Medical Center (IL), Masaryk Memorial Cancer Institute (CZ), Institute of Oncology NN Petrov (RU), Cancer Research Institute Ghent (BE), Evanston Hospital (US), National Institute of Oncology (HU), Monash Health (AU), Centre François Baclesse (FR), Fundación Pública Galega de Medicina Xenómica (ES), Mayo Clinic in Arizona (US), Cancer Research Center (US), Vall d'Hebron Hospital Universitari (ES), UPMC Hillman Cancer Center (US), University of Kansas Medical Center (US), Shaukat Khanum Memorial Cancer Hospital and Research Center (PK), Hospital Universitario Fundación Jiménez Díaz (ES), Istituto di Genetica Molecolare (IT), Cancer Registry of Norway (NO), Sinai Health System (CA), Providence Medford Medical Center (US), N.N. Alexandrov National Cancer Centre (BY), National Cancer Institute (US), Westmead Institute for Medical Research (AU), Cancer Genetics (United States) (US), Kliniken Essen-Mitte (DE), Instituto de Investigación Sanitaria de Santiago (ES), Erasmus MC Cancer Institute (NL), Institut Paoli-Calmettes (FR), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Io Therapeutics (United States) (US), Duke University Hospital (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Cologne (DE), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Research Network (United States) (US), Servicio Gallego de Salud (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), MRC Epidemiology Unit (GB), Economic & Social Sciences, Health Systems & Medical Informatics (FR), Instituto de Investigación de Enfermedades Raras (ES), Institut de Recherche pour le Développement (FR), Université Laval (CA), Vall d'Hebron Institute of Oncology (ES), Beckman Research Institute, UCLA Jonsson Comprehensive Cancer Center, Rutgers Cancer Institute (US), Division of Cancer Epidemiology and Genetics, University of Bergen (NO), University of Florence (IT), University College London (GB), Imperial College London (GB), University of Virginia (US), University of Colorado Anschutz Medical Campus (US), The Ohio State University (US), Monash University (AU), European Institute of Oncology (IT), Université de Rouen Normandie (FR), Universidad Autónoma de Madrid (ES), École Nationale Supérieure des Mines de Paris (FR), Medical University of Vienna (AT), University of Glasgow (GB), University of Pennsylvania (US), Pomeranian Medical University (PL), Institut Curie (FR), University of Gothenburg (SE), Aalborg University (DK), Vanderbilt University Medical Center (US), Leipzig University (DE), Cancer Council NSW (AU), Stanford University (US), Icahn School of Medicine at Mount Sinai (US), KU Leuven (BE)
U.S. Department of Defense, American Cancer Society, Susan G. Komen for the Cure, Breast Cancer Research Foundation, Oak Foundation, Ovarian Cancer Research Fund, Fisher Center for Alzheimer's Research Foundation, Minnesota Ovarian Cancer Alliance, AstraZeneca, GlaxoSmithKline, State of Connecticut Department of Public Health, Beth Israel Deaconess Medical Center, Vanderbilt University, Oregon Health and Science University, University of Pennsylvania, Ohio State University, Mayo Foundation for Medical Education and Research, Memorial Sloan-Kettering Cancer Center, Vanderbilt-Ingram Cancer Center, University of Chicago, Univerzita Karlova v Praze, Lee Foundation, Rutgers Cancer Institute of New Jersey, Kansas Bioscience Authority, Dana-Farber Cancer Institute, University of Pittsburgh, Fundación Mutua Madrileña, Georgetown University, Beckman Research Institute, City of Hope, Helsingin ja Uudenmaan Sairaanhoitopiiri, McGill University, Dr. Ralph and Marian Falk Medical Research Trust, Faculty of Medicine, McGill University, Deutsches Krebsforschungszentrum, Kreftforeningen, Genome Canada, Moffitt Cancer Center, Cancer Research Society, Japan Agency for Medical Research and Development, Wellcome Trust, Ministère du Développement Économique, de l’Innovation et de l’Exportation, Ovarian Cancer Australia, National Cancer Centre of Singapore, Royal Marsden NHS Foundation Trust, Swedish Cancer Foundation, Novocure, NorthShore University HealthSystem, Cedars-Sinai Medical Center, Génome Québec, QIMR Berghofer Medical Research Institute, Western Sydney Local Health District, Princeton Center for Complex Materials, Gray Foundation, Fondation du cancer du sein du Québec, Fred C. and Katherine B. Andersen Foundation, NRG Oncology, Amsterdam University Medical Centers, Lon V. Smith Foundation, Government of Canada, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, University of Cambridge, Imperial College London, University College London, European Commission, National Breast Cancer Foundation, Cancer Australia, Cancer Institute NSW, National Research Foundation, Cancer Association of South Africa, University of Pretoria, National Research Foundation Singapore, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Ministry of Education, Culture, Sports, Science and Technology, Universiteit Leiden, Rijksuniversiteit Groningen, Fundação de Amparo à Pesquisa do Estado de São Paulo, Radboud Universiteit, Vrije Universiteit Amsterdam, Universiteit Maastricht, Bundesministerium für Bildung und Forschung, Terry Fox Foundation, Cancerfonden, Generalitat de Catalunya, Erasmus Medisch Centrum, Universität Wien, Ministero della Salute, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Ministerio de Economía y Competitividad, Universitair Ziekenhuis Gent, Ministry of Health, Labour and Welfare, Ministério da Ciência, Tecnologia e Inovação, Hungarian Scientific Research Fund, University of Toronto, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Korea Health Industry Development Institute, Linköpings Universitet, Israel Cancer Association, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Odense Universitetshospital, Peter MacCallum Cancer Centre, Helse Vest, Vetenskapsrådet, Universiteit Gent, Lietuvos Mokslo Taryba, Maastricht Universitair Medisch Centrum, KWF Kankerbestrijding, Jewish General Hospital, NordForsk, Centre National de la Recherche Scientifique, Ministerio de Ciencia e Innovación, Umeå Universitet, Associazione Italiana per la Ricerca sul Cancro, Academic Center for Education, Culture and Research, Leids Universitair Medisch Centrum, Norges Forskningsråd, Sahlgrenska Universitetssjukhuset, Deutsche Krebshilfe, Radboud Universitair Medisch Centrum, Sigrid Juséliuksen Säätiö, Institut National Du Cancer, Clalit Health Services, Russian Science Foundation, Uppsala Universitet, European Society for Medical Oncology, Ministero dello Sviluppo Economico, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, Pomorski Uniwersytet Medyczny W Szczecinie, Istituto Oncologico Veneto, Syöpäsäätiö, Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Liga Portuguesa Contra o Cancro, Universität Innsbruck, Hebei Medical University, PharmaMar, Centro de Investigación Biomédica en Red de Cáncer, Institut Català de la Salut, Freistaat Sachsen, BC Cancer Foundation, Všeobecná Fakultní Nemocnice v Praze, Hellenic Health Foundation, Kerry Group Kuok Foundation, Unicancer, Peter MacCallum Foundation, National Institutes of Health, Directorate for Biological Sciences, University of California, Los Angeles, University of Texas MD Anderson Cancer Center, Fox Chase Cancer Center, University of California, San Francisco, Merck Sharp and Dohme, Cancer Center, University of Kansas, Health Canada, Canadian Institutes of Health Research, Medical Research Council, World Cancer Research Fund, National Health and Medical Research Council, Cancer Council Victoria, National Medical Research Council, Japan Society for the Promotion of Science, Instituto de Salud Carlos III, National Council for Scientific Research, European Regional Development Fund, NIHR Cambridge Biomedical Research Centre, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Jonsson Comprehensive Cancer Center, European Social Fund, Medical Research and Materiel Command, Common Fund
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BRCA gene mutations in cancer
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