Abstract
PURPOSE: The complex etiological variables and high heterogeneity of bladder cancer (BC) make prognostic prediction challenging. We aimed to develop a robust and promising gene signature using advanced machine learning methods for predicting the prognosis and therapy responses of BC patients. METHODS: The single-sample gene set enrichment analysis (ssGSEA) algorithm and univariable Cox regression were used to identify the primary risk hallmark among the various cancer hallmarks. Machine learning methods were then combined with survival and differential gene expression analyses to construct a novel prognostic signature, which would be validated in two additional independent cohorts. Moreover, relationships between this signature and therapy responses were also identified. Functional enrichment analysis and immune cell estimation were also conducted to provide insights into the potential mechanisms of BC. RESULTS: Epithelial-mesenchymal transition (EMT) was identified as the primary risk factor for the survival of BC patients (HR=1.43, 95% CI: 1.26-1.63). A novel EMT-related gene signature was constructed and validated in three independent cohorts, showing stable and accurate performance in predicting clinical outcomes. Furthermore, high-risk patients had poor prognoses and multivariable Cox regression analysis revealed this to be an independent risk factor for patient survival. CD8+ T cells, Tregs, and M2 macrophages were found abundantly in the tumor microenvironment of high-risk patients. Moreover, it was anticipated that high-risk patients would be more sensitive to chemotherapeutic drugs, while low-risk patients would benefit more from immunotherapy. CONCLUSIONS: We successfully identified and validated a novel EMT-related gene signature for predicting clinical outcomes and therapy responses in BC patients, which may be useful in clinical practice for risk stratification and individualized treatment.