GWAS meta-analysis identifies five susceptibility loci for endometrial cancer

Ramachandran D, Wang X, Laisk T, Zheng Y, Ingold N, Canson DM, Kho PF, Naumann BJ, Chapman CJ, Bousset K, Krause AV, Schürmann P, Wieland B, Hanel P, Hülse F, Häfner N, Runnebaum I, Dubrowinskaja N, Turmanov N, Yugay T, Yessimsiitova ZB, Amant F, Annibali D, Beckmann M, Bodelon C, Buchanan DD, Chen C, Clarke MA, Cook LS, De Vivo I, De Wispelaere W, Du M, Easton DF, Emons J, Fasching P, Friedenreich CM, Gallagher G, Giles GG, Goode EL, Harris HR, Hunter DJ, Kolin DL, Kraft P, Lacey JV, Lambrechts D, Lu L, Mutter GL, Naduparambil J, O'Connell K, Patel AV, Pharoah PD, Rebbeck TR, Ricceri F, Risch HA, Rübner M, Sacerdote C, Scott RJ, Setiawan VW, Shu XO, Southey MC, Tham E, Tomlinson I, Turman C, Wentzensen N, Xu W, Yu H, Zheng W, Spurdle AB, Yarden Y, Mägi R, Hillemanns P, Glubb DM, Dörk T, O'Mara TA (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 118

Article Number: 105830

DOI: 10.1016/j.ebiom.2025.105830

Abstract

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.

Authors with CRIS profile

Involved external institutions

Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Tartu Estonia (EE) Universitätsklinikum Jena Germany (DE) Alberta Health Services (AHS) Canada (CA) Memorial Sloan Kettering Cancer Center United States (USA) (US) Cancer Council Victoria Australia (AU) City of Hope Medical Center United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Yale University United States (USA) (US) Harvard University United States (USA) (US) Mayo Clinic United States (USA) (US) Fred Hutchinson Cancer Research Center United States (USA) (US) Harvard T.H. Chan School of Public Health United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) Vanderbilt University Medical Center United States (USA) (US) Karolinska Institute Sweden (SE) University of Oxford United Kingdom (GB) Fudan University / 复旦大学 China (CN) University of Hawaii (U.H.) United States (USA) (US) Weizmann Institute of Science Israel (IL) American Cancer Society United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Al-Farabi Kazakh National University / Äl Farabï atındağı Qazaq Ulttıq Unïversïteti Kazakhstan (KZ) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) The University of Melbourne Australia (AU) John Hunter Hospital Australia (AU) University of Colorado Anschutz Medical Campus United States (USA) (US) University of Cambridge United Kingdom (GB) Keck School of Medicine of USC United States (USA) (US)

How to cite

APA:

Ramachandran, D., Wang, X., Laisk, T., Zheng, Y., Ingold, N., Canson, D.M.,... O'Mara, T.A. (2025). GWAS meta-analysis identifies five susceptibility loci for endometrial cancer. EBioMedicine, 118. https://doi.org/10.1016/j.ebiom.2025.105830

MLA:

Ramachandran, Dhanya, et al. "GWAS meta-analysis identifies five susceptibility loci for endometrial cancer." EBioMedicine 118 (2025).

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