Journal Article Epublish
PubMed: 41266372 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.
NPJ Genom Med 10(1):73
Authors: 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, Adalgeir Arason, Banu K Arun, Judith Balmaña, Elisa V Bandera, Rosa B Barkardottir, Lieke P V Berger, Amy Berrington de Gonzalez, Pascaline Berthet, Katarzyna Białkowska, Line Bjørge, Amie M Blanco, Marinus J Blok, Kristie A Bobolis, Natalia V Bogdanova, James D Brenton, Henriett Butz, Saundra S Buys, Maria A Caligo, Ian Campbell, Carmen Castillo, Kathleen B M Claes, Sarah V Colonna, Linda S 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 Foretova, Renée T Fortner, Florentia Fostira, Maria Cristina Foti … and 118 other authors
Affiliations
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- Department of Internal Medicine, Division of Human Genetics, Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
- Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
- Inserm U1331, Paris, France.
- Institut Curie, Paris, France.
- Mines Paris, Paris, France.
- PSL Research University, Paris, France.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
- Department of Medicine, University of California Irvine, Irvine, CA, USA.
- Department of Pathology, Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland.
- BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
- Department of Medical Oncology, University Hospital of Vall d'Hebron, Barcelona, Spain.
- Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
- Clinical Cancer Epidemiology, Institute of Cancer Research, London, UK.
- Département de Biopathologie, Centre François Baclesse, Caen, France.
- INSERM UMR1245 Cancer and Brain Genomics, Université de Rouen Normandie, Rouen, France.
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
- Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA.
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
- City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA.
- Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
- N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
- Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
- National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary.
- Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary.
- Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
- SOD Genetica Molecolare, University Hospital, Pisa, Italy.
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
- Cancer Research Institute Ghent, Ghent, Belgium.
- Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
- Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO, USA.
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
- Department of Pathology and Laboratory Medicine, Institute of Oncology and Maria Sklodowska-Curie Cancer Center, Warsaw, Poland.
- Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia.
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.
- Center for Medical Genetics, Endeavor Health, Evanston, IL, USA.
- The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
- Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
- Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
- 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.
- Genomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
- Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway.
- Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
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.
MeSH
3' Untranslated Regions, Ovary, Neoplasms, Genome-Wide Association Study, Genome, Ovarian Neoplasms