Abstract PR001: Highlighting the combined effects of BMI and polygenic risk score on endometrial cancer risk

Abstract Obesity is more strongly associated with endometrial cancer risk than any other cancer type. However, the extent to which genetic susceptibility influences the risk of endometrial cancer independent of obesity remains unknown. Thus, this study aimed to evaluate the predictive performance of polygenic risk score (PRS), body mass index (BMI) and other factors in determining endometrial cancer risk, as well as to explore joint effects on endometrial cancer. PRS was generated using 1. 1 million HapMap3 variants from the largest published endometrial cancer genome-wide association study. An endometrial cancer prediction model was constructed using established endometrial cancer risk factors (age, BMI, number of live births, ever taken oral contraceptive pill, age of menarche, and predicted age of menopause). Additionally, an integrated prediction model was constructed, combining the endometrial cancer PRS with established risk factors. The ability of models to predict endometrial cancer status was assessed in unrelated participants of European ancestry from the UK Biobank cohort, encompassing 1, 867 participants with endometrial cancer (860 incident cases) and 133, 322 cancer-free controls. The integrated model including PRS and risk factors had a modest yet statistically significant improvement in prediction of endometrial cancer status, compared with the model using risk factors alone (AUC 0. 752 versus 0. 741; P = 1. 28 × 10−7). When examining incident cases, participants in the middle and top tertiles of the PRS distribution had a 1. 96- (95% CI 1. 39-2. 77; P = 1. 28 × 10−4) and 3. 03-fold (95% CI 2. 01-4. 58; P = 1. 60 × 10−8) elevated risk of developing endometrial cancer, respectively, in contrast to those in the lowest tertile. As expected, elevated BMI was associated with increased endometrial cancer risk. Compared to participants with a normal BMI, overweight participants (25kg/m2 ≤ BMI 30kg/m2) had a 1. 58-fold increased hazard ratio (HR; 95% CI 1. 32-1. 90; P = 8. 43 × 10−7), while obese participants (BMI ≥ 30kg/m2) a 3. 23-fold increased HR (95% CI 2. 71-3. 85; P 2. 00 × 10−16). Notably, we observed multiplying effects of BMI and PRS on endometrial cancer risk, with obese participants in the top tertile of the PRS distribution having a 7. 53-fold increased HR (95% CI 3. 78-14. 99; P = 9. 41 × 10−9). In summary, these findings indicate that higher PRS was associated with endometrial cancer risk, irrespective of BMI. Moreover, the integration of PRS with established risk factors may aid in better stratifying the general population for their susceptibility to endometrial cancer. Citation Format: Tracy A. O'Mara, Xuemin Wang, Laure Dossus, Marc J. Gunter, Emma J. Crosbie, Dylan M. Glubb. Highlighting the combined effects of BMI and polygenic risk score on endometrial cancer risk abstract. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30 (5Suppl): Abstract nr PR001.