Causal effects of multiple exposures on endometrial cancer and its subtypes: A two-sample Mendelian randomized study

Background: Endometrial cancer (EC) is a common gynecological tumor in women, with complex causes. Some studies suggest that it is related to lifestyle, gastrointestinal diseases, reproductive factors, etc., but the causal relationship among them remains unclear. This study employed a two-sample Mendelian randomization method to investigate the causal relationship between these factors and EC. Methods: MR Analysis was conducted using publicly available GWAS data. Preliminary analysis was carried out using the IVW method, combined with the RAPS method to enhance robustness, and supplementary analysis was performed using MR-Egger, weighted median, simple mode and weighted mode. Heterogeneity and pleiotropy were evaluated by Cochran Q test, Leave-One-Out method, MR-Egger intercept test and MR-PRESSO method. Results: Ten exposure factors that constitute a causal relationship with EC and its subtypes were identified from aspects such as Lifestyle, Gastrointestinal disease, and Reproductive factors. Among them, Variation in diet, Salt added to food and Gastroesophageal reflux disease (GERD) were only positively correlated with the risk of endometrioid EC (ECEH). However, Ulcerative colitis and Comparative body size at age 10 were positively correlated with both ECEH and non-endometrioid EC (ECNEH). Furthermore, Average weekly beer plus cider intake, Celiac disease, Age first had sexual intercourse and Length of menstrual cycle were negatively correlated with ECEH only, while Parental longevity (mother's attained age) was negatively correlated with both ECEH and ECNEH. Conclusion: Our mendelian randomization analysis provides genetic evidence supportive of potential causal roles for ten exposure factors in the development of endometrial cancer subtypes (ECEH and ECNEH). These findings suggest that early screening for populations with relevant risk profiles and targeted interventions for modifiable factors could be considered in future strategies for the subtype-specific prevention and management of endometrial cancer. Further validation in clinical and experimental settings is required.