GWAS meta-analysis identifies five susceptibility loci for endometrial cancer
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. 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. 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. 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. 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.
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eBioMedicineInstitutions
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Funding
PathologyAustralian Institute of Health and Welfare, Australian Government FundingNational Health and Medical Research Council Grant APP1031333National Health and Medical Research Council Grant APP1109286National Health and Medical Research Council Grant APP1111246National Health and Medical Research Council Grant APP552402National Health and Medical Research Council Grant APP1061779National Health and Medical Research Council Grant APP177524National Health and Medical Research Council Grant APP1158083National Health and Medical Research Council Grant APP1173170NHMRC Grant GNT1194896Seventh Framework Programme FundingOvarian Cancer Research Fund FundingGenome Canada FundingGenome-Wide Association Study of Endometrial CancerUS National Institutes of Health Grant CA1X01HG007491-01Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)Collaborative Genetic Study of Ovarian Cancer RiskThe Mitochondrial Genome and Ovarian Cancer RiskComprehensive molecular characterization of endometrial cancer, etiologic heterogeneity, and racial disparitiesWellcome Trust FundingCancer Research UK FundingEesti Teadusagentuur FundingMedizinischen Hochschule Hannover FundingVicHealth FundingUniversity of Melbourne FundingEuropean Research Council FundingCanadian Institutes of Health Research Grant MOP-86727Estonian Research and Development Council Grant PSG776National Cancer Institute Grant 2021.142.1Cancer Council Victoria Grant 209057Cancer Council Victoria Grant 396414Cancer Council Victoria Grant 1074383Wilhelm Sander Foundation Funding