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Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer
Daniel R. Barnes, Jonathan P. Tyrer, Joe Dennis, Goska Leslie, Manjeet K. Bolla, Michael Lush, Amber M. Aeilts, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Hoda Anton‐Culver, Aðalgeir Arason, Banu Arun, Judith Balmañà, Elisa V. Bandera, Rósa B. Barkardóttir, Lieke P. V. Berger, Amy Berrington de González, Pascaline Berthet, Katarzyna Białkowska, Line Bjørge, Amie Blanco, Marinus J. Blok, Kristie Bobolis, Natalia Bogdanova, James D. Brenton, Henriett Butz, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Carmen J. Contreras‐Castillo, Kathleen Claes, Sarah V. Colonna, Linda Cook, Mary B. Daly, Agnieszka Dansonka‐Mieszkowska, Miguel de la Hoya, Anna DeFazio, Allison DePersia, Yuan Chun Ding, Jennifer A. Doherty, Susan M. Domchek, Thilo Dörk, Zakaria Einbeigi, Christoph Engel, D. Gareth Evans, Lenka Foretová, Renée T. Fortner, Florentia Fostira, Maria Cristina Foti, Eitan Friedman, Megan N. Frone, Patricia A. Ganz, Aleksandra Gentry-Maharaj, Gord Glendon, Andrew K. Godwin, Anna González‐Neira, Mark H. Greene, Jacek Gronwald, Aliana Guerrieri‐Gonzaga, U. Hamann, Thomas van Overeem Hansen, Holly R. Harris, Jan Hauke, Florian Heitz, Maartje J. Hooning, John L. Hopper, Chad Huff, David Huntsman, Evgeny N. Imyanitov, Louise Izatt, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Siddhartha Kar, Beth Y. Karlan, Catherine J. Kennedy, Lambertus A. Kiemeney, Irene Konstantopoulou, Jolanta Kupryjańczyk, Yael Laitman, Ofer Lavie, Kate Lawrenson, Jenny Lester, Fabienne Lesueur, Carlos Lopez-Pleguezuelos, Siranoush Manoukian, Taymaa May, Iain A. McNeish, Usha Menon, Roger L. Milne, Francesmary Modugno, Jennifer M. Mongiovi, Marco Montagna, Kirsten B. Moysich, Susan L. Neuhausen, Finn C. Nielsen, Catherine Noguès, Edith Oláh, Olufunmilayo I. Olopade, Ana Osório, Laura Papi, Harsh B. Pathak, Celeste Leigh Pearce, Inge Søkilde Pedersen, Ana Peixoto, Tanja Pejović, Pei-Chen Peng, Beth N. Peshkin, Paolo Peterlongo, C. Bethan Powell, Darya Prokofyeva, Miguel Ángel Pujana, Paolo Radice, Muhammad Usman Rashid, Gad Rennert, George Richenberg, Dale P. Sandler, Naoko Sasamoto, Veronica Wendy Setiawan, Priyanka Sharma, Weiva Sieh, Christian F. Singer, Katie Snape, Anna P. Sokolenko, Penny Soucy, Melissa C. Southey, D Stoppa-Lyonnet, Rebecca Sutphen, Christian Sutter, Yen Y. Tan, Manuel R. Teixeira, Kathryn L. Terry, Liv Cecilie Vestrheim Thomsen, Marc Tischkowitz, Amanda E. Toland, Toon Van Gorp, Ana Vega, Digna R. Velez Edwards, Penelope M. Webb, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Stacey J. Winham, Anna H. Wu, Siddhartha Yadav, Yao Yu, Argyrios Ziogas, Andrew Berchuck, Fergus J. Couch, Ellen L. Goode, Marc T. Goodman, Álvaro N.A. Monteiro, Kenneth Offit, Susan J. Ramus, Harvey A. Risch, Joellen M. Schildkraut, Mads Thomassen, Jacques Simard, Douglas F. Easton, Michelle R. Jones, Georgia Chenevix‐Trench, Simon A. Gayther, Antonis C. Antoniou, Paul D.P. Pharoah
Bibliographic record
Venuenpj Genomic Medicine · 2025
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicBRCA gene mutations in cancer
Canadian institutionsUniversité LavalUniversity of British ColumbiaSinai Health SystemVancouver General HospitalLunenfeld-Tanenbaum Research InstituteCentre hospitalier universitaire de QuébecPrincess Margaret Cancer CentreBC Cancer AgencyUniversity of Toronto
FundersMedical Research and Materiel CommandJonsson Comprehensive Cancer CenterNational Center for Research ResourcesNational Institute of Neurological Disorders and StrokeNational Institute of General Medical SciencesNIH Office of the DirectorNational Human Genome Research InstituteNational Institute of Mental HealthNational Cancer InstituteEuropean Regional Development FundCancer Council VictoriaCancer Center, University of KansasUniversity of California, San FranciscoUniversity of Texas MD Anderson Cancer CenterUniversity of California, Los AngelesNational Institutes of HealthUnicancerKerry Group Kuok FoundationDirectorate for Biological SciencesHellenic Health FoundationWorld Cancer Research FundBC Cancer FoundationFreistaat SachsenInstitut Català de la SalutCentro de Investigación Biomédica en Red de CáncerLiga Portuguesa Contra o CancroMutuelle Générale de l'Education NationaleHebei Medical UniversityInstitut Gustave-RoussyMinistero dello Sviluppo EconomicoEuropean Society for Medical OncologyCommon FundUppsala UniversitetClalit Health ServicesSigrid Juséliuksen SäätiöNational Health and Medical Research CouncilDeutsche KrebshilfeNational Medical Research CouncilNorges ForskningsrådPomorski Uniwersytet Medyczny W SzczecinieAcademic Center for Education, Culture and ResearchCentre National de la Recherche ScientifiqueFox Chase Cancer CenterKWF KankerbestrijdingNational Council for Scientific ResearchMaastricht Universitair Medisch CentrumMerck Sharp and DohmeVetenskapsrådetHelse VestNational Institute on Drug AbuseOdense UniversitetshospitalLigue Contre le CancerLinköpings UniversitetCancer Association of South AfricaHungarian Scientific Research FundSwedish Cancer FoundationMinistry of Health, Labour and WelfareUniversität WienCancerfondenTerry Fox FoundationVrije Universiteit AmsterdamRijksuniversiteit GroningenMinistero della SaluteInstitut National de la Santé et de la Recherche MédicaleNational Research Foundation SingaporeNederlandse Organisatie voor Wetenschappelijk OnderzoekDeutsche ForschungsgemeinschaftAmerican Cancer SocietyRadboud UniversiteitCancer AustraliaCancer Institute NSWNIHR Cambridge Biomedical Research CentreUniversity College LondonUniversity of TorontoMinisterio de Ciencia e InnovaciónMcGill UniversityUniverzita Karlova v PrazeGeneralitat de CatalunyaFondation ARC pour la Recherche sur le CancerImperial College LondonNational Research FoundationJewish General HospitalNational Institute for Health and Care ResearchNRG OncologyUniversity of CambridgeNemzeti Kutatási Fejlesztési és Innovációs HivatalGovernment of CanadaGenome CanadaGlaxoSmithKlineFred C. and Katherine B. Andersen FoundationRussian Science FoundationGray FoundationPrinceton Center for Complex MaterialsWestern Sydney Local Health DistrictPharmaMarAssociazione Italiana per la Ricerca sul CancroAmsterdam University Medical CentersQIMR Berghofer Medical Research InstituteFondation du cancer du sein du QuébecGénome QuébecCanadian Institutes of Health ResearchLietuvos Mokslo TarybaEuropean CommissionCedars-Sinai Medical CenterDepartment of Health and Social CareNorthShore University HealthSystemUniversitair Ziekenhuis GentOvarian Cancer AustraliaFaculty of Medicine, McGill UniversityPeter MacCallum FoundationHelsingin ja Uudenmaan SairaanhoitopiiriIstituto Oncologico VenetoInstitut National Du CancerKreftforeningenMemorial Sloan-Kettering Cancer CenterUniversität InnsbruckWellcome TrustMinistry of Education, Culture, Sports, Science and TechnologyBeckman Research Institute, City of HopeLon V. Smith FoundationRutgers Cancer Institute of New JerseyMinistère du Développement Économique, de l’Innovation et de l’ExportationFundación Mutua MadrileñaNational Heart, Lung, and Blood InstituteUniversiteit LeidenOhio State UniversityKorea Health Industry Development InstituteVanderbilt UniversityState of Connecticut Department of Public HealthUniversity of ChicagoIsrael Cancer AssociationDr. Ralph and Marian Falk Medical Research TrustVanderbilt-Ingram Cancer CenterJapan Agency for Medical Research and DevelopmentConselho Nacional de Desenvolvimento Científico e TecnológicoBreast Cancer Research FoundationDana-Farber Cancer InstituteUniversiteit GentNational Breast Cancer FoundationHealth CanadaNovocureEuropean Social FundMedical Research CouncilMayo Foundation for Medical Education and ResearchUniversity of PennsylvaniaDeutsches KrebsforschungszentrumCancer Research SocietyMinistério da Ciência, Tecnologia e InovaçãoUmeå UniversitetMoffitt Cancer CenterMinnesota Ovarian Cancer AllianceRadboud Universitair Medisch CentrumUniversity of PretoriaCancer Research UKNordForskU.S. Department of DefenseLeids Universitair Medisch CentrumOak FoundationPeter MacCallum Cancer CentreFisher Center for Alzheimer's Research FoundationErasmus Medisch CentrumMinisterio de Economía y CompetitividadNational Center for Advancing Translational SciencesBundesministerium für Bildung und ForschungJapan Society for the Promotion of ScienceOvarian Cancer Research FundSahlgrenska UniversitetssjukhusetRoyal Marsden NHS Foundation TrustInstituto de Salud Carlos IIILee FoundationOregon Health and Science UniversityUniversiteit MaastrichtUniversity of PittsburghVšeobecná Fakultní Nemocnice v PrazeKansas Bioscience AuthoritySyöpäsäätiöFundação de Amparo à Pesquisa do Estado de São PauloAstraZenecaBeth Israel Deaconess Medical CenterSusan G. Komen for the CureNational Cancer Centre of SingaporeGeorgetown University
KeywordsOvarian cancerGenome-wide association studyOdds ratioSerous fluidSNPBiobankSerous ovarian cancer
Abstract
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.431
Threshold uncertainty score0.842
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.009
GPT teacher head0.262
Teacher spread0.252 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
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Citations0
Published2025
Admission routes2
Has abstractyes