Risk Stratification for Endometrial Cancer Reveals Independent Contributions of Polygenic Risk and Body Mass Index

BackgroundObesity is a major risk factor for endometrial cancer, but it is unknown whether it impacts the association between genetic risk and endometrial cancer. We incorporated polygenic risk score and epidemiological risk factors in the prediction of and investigated associations of BMI and polygenic risk score with endometrial cancer risk MethodsWe generated polygenic risk score for endometrial cancer in 129,829 unrelated female participants of European ancestry (including 956 incident cases with endometrial cancer) in the UK Biobank and predicted endometrial cancer using endometrial cancer polygenic risk score and established epidemiological risk factors, including BMI. We evaluated the performance of endometrial cancer prediction models by odds ratios and area under the receiver operating characteristic curves (AUCs) to using logistic regression. Individual and joint associations of BMI and polygenic risk score with endometrial cancer were assessed using Cox proportional hazards models. ResultsAn integrated model incorporating both polygenic risk score and epidemiological risk factors achieved a modest, but statistically significant, improvement in predicting endometrial cancer status compared with the model that included epidemiologic risk factors alone (AUC = 0.74 versus 0.73; P = 3.98 x 10-5). Obese participants (BMI [≥] 30 kg/m2) in the top polygenic risk tertile had the highest endometrial cancer risk. We observed independent effects of genetic risk and BMI on endometrial cancer risk. ConclusionIntegrating polygenic risk score with epidemiological risk factors may offer insights into population stratification for endometrial cancer susceptibility. Higher endometrial cancer polygenic risk is associated with endometrial cancer, irrespective of BMI.