Abstract
BackgroundDepicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues.MethodsIn this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score.ResultsTwo 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the β-catenin, FGFR3, and PPAR-γ pathways.ConclusionsThe novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers.
Highlights
Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA)
We evaluated the accuracy of the 5mC score in predicting classical molecular subtypes by using receiver operator curves (ROCs)
Landscape and multiomics analysis of 5mC regulators in BLCA 5mC is a dynamic and reversible process mediated by several distinct regulators that plays critical roles in various biological processes in cancers (Fig. S1A)
Summary
Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). The prognosis of advanced BLCA is poor, despite promising progress in immune checkpoint blockade (ICB), neoadjuvant chemotherapy, and targeted therapy [5]. This is because a majority of BLCA patients are not sensitive to these therapies, and there are no robust and efficient biomarkers or tools to accurately predict the clinical response to those treatments.
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