Functional investigation and two-sample Mendelian randomization study of bladder cancer-related genes: focus on gender differences

Abstract

Objective Bladder cancer is a common malignant tumor. There is a significant gender difference in the incidence rate, and the pathogenesis has not yet been clarified. The objective of this study was to explore the potential pathogenic genes of bladder cancer, measure the expression of these genes in patients of different sexes, and apply these genes to predict the risk of bladder cancer in clinical practice. Methods Genes related to the pathogenesis of bladder cancer were obtained by differential expression analysis and weighted gene co-expression network analysis (WGCNA). Key genes were obtained by intersection. Then, we analyzed the biological functions of key genes through KEGG and GO and constructed a PPI network to screen hub genes and generate a nomograph model to predict the risk of bladder cancer. The correlation between VEGFA and immune cell infiltration in bladder cancer was evaluated by immunocyte infiltration analysis. Finally, a two-sample Mendelian randomization study was conducted to determine the causal effect of VEGFA on bladder cancer. Results We obtained 376 key genes in the male bladder cancer group and 328 key genes in the female bladder cancer group. GO and KEGG analyses showed differences in the biological functions of these genes between male and female patients. Using the expression profile of the hub genes (CAV1, VEGFA, COL3A1, MYL9, and COL1A2 in males and COL3A1, ACTA2, TPM2 TPM1, and COL1A2 in females), we constructed a nomogram model to predict the risk of bladder cancer for males and females, respectively. In addition, the ROC curve showed that the model is effective in predicting bladder cancer. Besides, we found that there was a significant correlation between the expression of VEGFA and immune cell infiltration in male bladder cancer, but not in female patients. Finally, the Mendelian randomized study showed that there was a causal relationship between VEGFA and bladder cancer risk. Conclusion There are gender differences in the expression level and biological function of bladder cancer-related genes. We found that VEGFA has a causal relationship with the risk of bladder cancer, which may provide new insights into the diagnosis and treatment of bladder cancer.