Introduction/Background Endometrial cancer (EC) is the most common gynaecological cancer in high income countries and its incidence is rising globally. Genetic susceptibility of EC have been linked with several loci of common variants, however, these only explained ~10% genetic background and the overall contribution of rare coding variants to EC is unclear.

Methodology Here, we performed exome-wide association study to evaluate the penetrance of rare coding variants on cross-ancestry datasets. The UK Biobank conprised of 1,587 EC cases and 159,324 non-cancer controls from Gaussian ancestry. Burden tests from the STAAR pipeline were applied to identify novel genes with excess pathogenic loss-of-function (pLOF) and disruptive missense (d-mis) variants in EC. We replicated these results on in house Chinese EC cohort of 239 patients compared with 10,588 Chinese controls from ChinaMAP. In vitro experients were used to assess effects of these genes.

Results Associations between pLOF as well as pLOF plus d-mis (pLOF_ds) variants and EC identified 50 and 26 genes at exome-wide significance (p < 2.5*10–6), respectively, including known EC susceptibility genes MSH6 and MSH2. These results were replicated in Chinese cohort, revealing X genes also contributing to EC in East Asia population. In vitro silence of these genes through small interfering RNA (siRNA) suggested that functional silence of these genes would result in decreased proliferation rates and migration capacity.

Conclusion We uncovered novel EC risk genes across European and Asia population and validated their functions. This would provide new insights on genetic background of EC and pave the way for screening of EC.

Disclosures The authors declare no competing interests.