Shihao Hong

Genetic evidence linking anti-polyomavirus 2 IgG seropositivity to ovarian cancer risk

Antibody-related immune phenotypes reflect long-term host–pathogen interactions and immunogenetic regulation, and have been increasingly implicated in cancer susceptibility. In ovarian cancer, observational associations between immune responses and disease risk remain difficult to interpret due to confounding and potential reverse causation. Genetic analyses may help clarify whether specific antibody immune response profiles are linked to ovarian cancer risk. We investigated the associations between 46 genetically predicted antibody immune response phenotypes and ovarian cancer using a 2-sample Mendelian randomization framework. Genetic instruments for antibody traits were obtained from large genome-wide association studies, while ovarian cancer summary statistics were derived independently from the FinnGen R12 and OpenGWAS resources. Causal estimates were derived primarily using inverse-variance weighted models and subsequently synthesized across datasets to improve precision. Multiple testing adjustment was applied, and additional analyses were conducted to assess robustness and causal directionality. Across the evaluated antibody phenotypes, most showed no evidence of a causal association with ovarian cancer risk. After meta-analysis and correction for multiple comparisons, genetically predicted anti-polyomavirus 2 immunoglobulin G (IgG) seropositivity was associated with a modest increase in ovarian cancer risk (odds ratio = 1.062, 95% confidence interval: 1.027–1.099). Sensitivity analyses did not indicate substantial pleiotropic bias, and reverse-direction analyses provided no support for ovarian cancer influencing anti-polyomavirus 2 IgG levels. These findings suggest that genetic liability to anti-polyomavirus 2 IgG seropositivity, as a marker of immune response rather than active infection, is modestly associated with ovarian cancer risk in individuals of European ancestry. Although the effect size is small, the results highlight a potential role for antibody-mediated immune processes in ovarian cancer etiology and warrant further investigation in diverse populations and experimental settings.

Causal Relationships Between Pregnancy, Menstrual History, and Endometrial Cancer With Mediating Effects of Metabolism‐Related Traits

Background Periods and pregnancy may affect the development of endometrial cancer by affecting the secretion of sex hormones, but the causal relationship is not clear, and its mediating factors need to be explored. Methods In this study, multivariable Mendelian randomization was used to analyze summary statistics of genome‐wide association studies of European ancestry, to evaluate the effect of 10 period‐ or pregnancy‐related factors on endometrial cancer. In addition, we performed the heterogeneity test and pleiotropy test to analyze the sensitivity. Because of the effect of sex hormones on body metabolism and the relationship between metabolism‐related traits and cancer, we explored the mediating effect of metabolism‐related traits by two‐step Mendelian randomization. Results This study showed that age at menarche ( p = 1.21e − 05; OR = 0.6852; 95% CI: 0.5784–0.8116), age at menopause ( p = 0.00098; OR = 1.242; 95% CI: 1.0919–1.4127), and sex hormone–binding globulin (SHBG) levels ( p = 7.4e − 07; OR = 0.5914; 95% CI: 0.4804–0.7281) have an independent causal relationship with the incidence of endometrial cancer. Moreover, several obesity‐related traits play a mediating role in the causal relationship between age at menarche and endometrial cancer. The mediators and their mediating effects are BMI (55.54%), obesity (30.37%), waist circumference preference (27.67%), body fat percentage (17.61%), and waist‐to‐hip ratio (14.82%). These results are robust to sensitivity analysis. Conclusion This study demonstrated the independent effect of pregnancy‐ and period‐related factors on endometrial cancer and suggested that avoiding obesity may be an effective method to prevent endometrial cancer for patients with premature menarche.