Absence of causal association between CD40-CD40L signaling and cervical cancer risk: A Mendelian randomization study

To investigate the potential causal relationship between cluster of differentiation 40 (CD40)-cluster of differentiation 40 ligand (CD40L) signaling and cervical cancer risk using a two-sample Mendelian randomization (MR) approach and to explore the expression and immune correlation of CD40/CD40L in cervical cancer. A two-sample MR framework was used in this study. Genetic instruments for CD40-CD40L (exposure) were derived from the plasma protein quantitative trait loci data. Summary-level data for cervical cancer (outcome) were obtained from 5 independent genome-wide association study datasets. Instrumental variable selection adhered to the core MR assumptions. Causal estimates were primarily generated using the inverse-variance weighted method supplemented by MR-Egger, weighted median, and other sensitivity analyses. Heterogeneity and pleiotropy were assessed. Bioinformatics analyses using the Sangerbox 3.0 and Gene Expression Profiling Interactive Analysis 2 databases were used to evaluate the expression, prognostic value, and immune infiltration correlation of CD40 and CD40L in cervical squamous cell carcinoma and endocervical adenocarcinoma. MR analyses found no significant causal effect of CD40-CD40L signaling on cervical cancer risk across all datasets (e.g., for CD40: inverse-variance weighted OR = 1.014, P = .838). Sensitivity analyses, including leave-one-out validation and tests for heterogeneity and horizontal pleiotropy, supported the robustness of null findings. Expression analysis showed no significant difference in CD40/CD40L mRNA levels between tumor and normal tissues and no correlation with overall survival. However, their expression was positively correlated with stromal, immune, and ESTIMATE scores in the tumor microenvironment. This MR study found no genetic evidence to support a causal role for CD40-CD40L signaling in cervical cancer etiology. Although not a causal risk factor, the positive correlation of CD40/CD40L expression with immune microenvironment scores suggests a potential role in local immune regulation, warranting further investigation.