A Polygenic Risk Score-Based Genetic Stratification For Endometrial Cancer

Endometrial cancer (EC) is the most common of gynecological cancers in the UK. There is evidence for genetic predisposition to EC, however, single nucleotide polymorphisms have not been considered in risk prediction models so far. We hypothesized that a polygenic risk score (PRS) based on a panel of robust SNPs may be useful to predict women at high risk of developing EC. We conducted a systematic review to identify the most robust SNPs which may be associated with EC risk. The resulting panel of SNPs was validated in an independent cohort comprising EC cases, and control women with intact uterus. In the present study, we used 560 cases and 1202 controls of broad-European origin to construct a PRS. Our systematic review suggested twenty four SNPs, nineteen of which were reported to reach genome-wide significance in large GWAS. Preliminary results using 560 cases and 1202 controls produced effect sizes, directions and dosages similar to published data. The mean PRS for EC cases was 0.64 (SD=0.43, 95%CI 0.60-0.68) while mean PRS for controls was 0.48 (SD=0.42, 95% CI 0.46-0.51). The AUC of the PRS achieved was 0.61. Women in the highest tertile of the PRS score had a 2.4 times increased risk of developing EC compared to women in the lowest tertile (OR=2.40, 95%CI 1.85-3.09, p = 1.47E-11). Women in the mid tertile also had a modestly increased risk of EC compared to the lowest tertile (OR=1.40, 95%CI 1.06-1.84, p = 0.017). There was a clear trend of increasing risk with category (p = 6.25E-12). There is mounting evidence for polygenic input from common variants in EC susceptibility. Our results, for the first time, validate the potential use of a PRS for risk stratification of women at high risk of EC. When considered alongside epidemiological risk factors, the PRS could provide a good discrimination for early detection and prevention of EC in a clinical setting. Citation Format: Cemsel Bafligil, Deborah J. Thompson, Artitaya Lophatananon, Miriam J. Smith, Joe Dennis, Gareth D. Evans, Emma J. Crosbie. A polygenic risk score-based genetic stratification for endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2322.