Causal association between Epstein–Barr virus infection and malignant gynecologic and breast tumors: a two-sample Mendelian randomization study

To explore the causal association between genetically predicted Epstein–Barr virus (EBV) infection and breast, cervical, endometrial, and ovarian cancers. Public data from genome-wide association studies of EBV infection and cancers were used to perform a two-sample Mendelian randomization (MR) study. The inverse variance weighted (IVW) method was the main analysis method, while the weighted median, weighted mode, and MR-Egger methods were used to test the robustness of the IVW results. Cochran’s Q-test, MR-Egger regression, MR-PRESSO, and leave-one-out methods were used to detect heterogeneity, horizontal pleiotropy, outliers, and SNPs driving the results, respectively. There were no statistically significant causal associations between genetically predicted EBV infection and genetically predicted endometrial (OR = 1.55, 95%CI: 0.71–3.37, P = 0.27), cervical (OR = 0.96, 95%CI: 0.42–2.22, P = 0.93), ovarian (OR = 1.55, 95%CI: 0.72–3.33, P = 0.26), or breast (OR = 1.02, 95%CI: 0.79–1.33, P = 0.85) cancers. The raw MR-PRESSO analyses support the IVW results but detected one outlier for the endometrial cancer analysis. After removing the outlier, a suggestive association was observed between EBV infection and endometrial cancer (OR = 2.43, 95%CI: 1.19–4.95, P = 0.024). Cochran’s Q-test detected heterogeneity for endometrial cancer (P = 0.04). The MR-Egger regression analysis revealed no horizontal pleiotropy. The leave-one-out analysis revealed no SNPs driving the results by themselves. This MR study showed a possible causal association between EBV infection and the risk of endometrial cancer. This association warrants additional study.