Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility

Genome-wide association studies (GWAS) of endometrial cancer have identified 16 genetic susceptibility loci. To identify candidate endometrial cancer susceptibility genes, we have performed the first transcriptome-wide association study (TWAS) of endometrial cancer. For this analysis, we have used the largest endometrial cancer GWAS and gene expression from 48 tissues to maximise statistical power. We used colocalisation analysis to prioritise seven candidate susceptibility genes, including CYP19A1 , which wes previously established as an endometrial cancer susceptibility gene. Notably, one of the candidate susceptibility genes was located at 17q24.2, a potentially novel risk locus for endometrial cancer. Using phenome-wide association analysis, candidate susceptibility genes were found to associate with traits related to endometrial cancer risk factors, in addition to other clinical phenotypes that may provide novel risk factors. TWAS data were also used to perform drug repurposing analysis and identified 14 compounds; two of these are tubulin inhibitors, a drug class used to treat advanced endometrial cancer. In summary, this study has revealed biologically relevant endometrial cancer susceptibility genes, providing insights into endometrial cancer aetiology and avenues for the development of new treatments.