GWAS meta-analysis identifies five susceptibility loci for endometrial cancer
Ramachandran D. Wang X. Laisk T. Zheng Y. Ingold N. Canson D.M. Kho P.F. Naumann B.J. Chapman C.J. Bousset K. Krause A.V. Schürmann P. Wieland B. Hanel P. Hülse F. Häfner N. Runnebaum I. Dubrowinskaja N. Turmanov N. Yugay T. Yessimsiitova Z.B. Amant F. Annibali D. Beckmann M.W. Bodelon C. Buchanan D.D. Chen C. Clarke M.A. Cook L.S. De Vivo I. De Wispelaere W. Du M. Easton D.F. Emons J. Fasching P.A. Friedenreich C.M. Gallagher G. Giles G.G. Goode E.L. Harris H.R. Hunter D.J. Kolin D.L. Kraft P. Lacey J.V. Lambrechts D. Lu L. Mutter G.L. Naduparambil J. OConnell K. Patel A.V. Pharoah P.D.P. Rebbeck T.R. Ricceri F. Risch H.A. Ruebner M. Sacerdote C. Scott R.J. Setiawan V.W. Shu X.-O. Southey M.C. Tham E. Tomlinson I. Turman C. Wentzensen N. Xu W. Yu H. Zheng W. Spurdle A.B. Yarden Y. Mägi R. Hillemanns P. Glubb D.M. Dörk T. OMara T.A.
August 2025Elsevier B.V.
eBioMedicine
2025#118
Background: Endometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined. Methods: Building on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan. Findings: GWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells. Interpretation: Our large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer. Funding: This study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.
Endometrial carcinoma , eQTL , GWAS , Luciferase , NAV3
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Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
Cancer Research Program, QIMR Berghofer, Brisbane, QLD, Australia
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
Department of Gynecology, The First Hospital of Hebei Medical University, Shijiazhuang, China
Population Health Program, QIMR Berghofer, Brisbane, QLD, Australia
Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
RU21 GmbH, Jena, Germany
Clinic for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
Rahat Clinics, Almaty, Kazakhstan
KRH Clinic Neustadt am Rübenberge, Neustadt am Rübenberge, Germany
Department of Biodiversity and Bioresources, al-Farabi Kazakh National University, Almaty, Kazakhstan
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals KU Leuven, University of Leuven, Leuven, Belgium
Gynecological Oncology Laboratory, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany
Department of Population Science, American Cancer Society, Atlanta, GA, United States
Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia
Collaborative Centre for Genomic Cancer Medicine, Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia
Epidemiology Program, Fred Hutchinson Cancer Center, Seattle, WA, United States
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
Epidemiology, School of Public Health, University of Colorado, Aurora, CO, United States
Community Health Sciences, University of Calgary, Calgary, AB, Canada
Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA, United States
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
Unit of Epidemiology, Local Health Unit of Novara, Novara, Italy
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom
Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, AB, Canada
Departments of Oncology and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, United States
Department of Epidemiology, University of Washington, Seattle, WA, United States
Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Brigham and Womens Hospital, Boston, MA, United States
Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, United States
City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, United States
Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
VIB Center for Cancer Biology, VIB, Leuven, Belgium
Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, United States
Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, United States
Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, United States
Harvard T.H. Chan School of Public Health, Boston, MA, United States
Dana-Farber Cancer Institute, Boston, MA, United States
Department of Clinical and Biological Sciences, Centre for Biostatistics, Epidemiology, and Public Health (C-BEPH), University of Turin, Turin, Italy
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy
Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, NSW, Australia
Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, NSW, Australia
Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States
Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden
Department of Oncology, University of Oxford, Oxford, United Kingdom
School of Public Health, Fudan University, Shanghai, China
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States
Weizmann Institute of Science, Rehovot, Israel
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
Gynaecology Research Unit
Cancer Research Program
Estonian Genome Center
Department of Gynecology
Population Health Program
Department of Gynaecology
RU21 GmbH
Clinic for Rheumatology and Immunology
Rahat Clinics
KRH Clinic Neustadt am Rübenberge
Department of Biodiversity and Bioresources
Division of Gynecologic Oncology
Gynecological Oncology Laboratory
Department of Gynecology and Obstetrics
Department of Population Science
Colorectal Oncogenomics Group
Collaborative Centre for Genomic Cancer Medicine
Epidemiology Program
Division of Cancer Epidemiology and Genetics
Epidemiology
Community Health Sciences
Channing Division of Network Medicine
Department of Epidemiology
Unit of Epidemiology
Department of Epidemiology and Biostatistics
Department of Oncology
Department of Public Health and Primary Care
Department of Cancer Epidemiology and Prevention Research
Departments of Oncology and Community Health Sciences
Cancer Epidemiology Division
Centre for Epidemiology and Biostatistics
Precision Medicine
Division of Epidemiology
Program in Epidemiology
Department of Epidemiology
Nuffield Department of Population Health
Brigham and Womens Hospital
Division of Cancer Epidemiology and Genetics
Department of Computational and Quantitative Medicine
City of Hope Comprehensive Cancer Center
Laboratory for Translational Genetics
VIB Center for Cancer Biology
Chronic Disease Epidemiology
Department of Medicine
Department of Computational Biomedicine
Harvard T.H. Chan School of Public Health
Dana-Farber Cancer Institute
Department of Clinical and Biological Sciences
Department of Health Sciences
Division of Molecular Medicine
Discipline of Medical Genetics
Hunter Medical Research Institute
Department of Preventive Medicine
Division of Epidemiology
Department of Clinical Pathology
Department of Molecular Medicine and Surgery
Clinical Genetics and Genomics
Department of Oncology
School of Public Health
Epidemiology Program
Weizmann Institute of Science
School of Biomedical Sciences
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