Integrative machine learning algorithms for developing a consensus RNA modification-based signature for guiding clinical decision-making in bladder cancer

Abstract Objectives Dysregulation of RNA modifications has emerged as a contributor to cancer, but the clinical implication of RNA modification-related genes remains largely unclear. The study focused on well-studied RNA modification modalities (m 6 A, m 1 A, m 5 C and m 7 G) in bladder cancer, and proposed a machine learning-based integrative approach for establishing a consensus RNA modification-based signature. Methods Multiple publicly available bladder cancer cohorts were enrolled. A novel RNA modification-based classification was proposed via consensus clustering analysis. RNA modification-related genes were subsequently selected through WGCNA. A machine learning-based integrative framework was implemented for constructing a consensus RNA modification-based signature. Results Most RNA modifiers were dysregulated in bladder tumours at the multi-omics levels. Two RNA modification clusters were identified, with diverse prognostic outcomes. A consensus RNA modification-based signature was established, which displayed stable and powerful efficacy in prognosis estimation. Notably, the signature was superior to conventional clinical indicators. High-risk tumours presented the activation of tumourigenic pathways, with the activation of metabolism pathways in low-risk tumours. The low-risk group was more sensitive to immune-checkpoint blockade, with the higher sensitivity of the high-risk group to cisplatin and paclitaxel. Genes in the signature: AKR1B1 , ANXA1 , CCNL2 , OAS1 , PTPN6 , SPINK1 and TNFRSF14 were specially expressed in distinct T lymphocytes of bladder tumours at the single-cell level, potentially participating in T cell-mediated antitumour immunity. They were transcriptionally and post-transcriptionally modulated, and might become potentially actionable therapeutic targets. Conclusions Altogether, the consensus RNA modification-based signature may act as a reliable and hopeful tool for improving clinical decision-making for individual bladder cancer patients.