Identification of a novel RNA modifications-related model to improve bladder cancer outcomes in the framework of predictive, preventive, and personalized medicine
Authors: Zhang Ziying , Chen Peng , Liu Fangyi , Lin Censhan , Deng Ru , Wu Liyan , Cao Yun , Yun Jingping , Huang Yuhua 
Published: April 2022

Background
Bladder cancer (BCa) is the leading reason for death among malignancies in genitourinary system. RNA modifications participate in pivotal tumor-promoting mechanisms in specific epigenetic contexts. Our study aimed to propose a novel model associated with the “writer” enzymes of five primary RNA adenosine modifications (including m6A, m6Am, m1A, alternative polyadenylation, and adenosine-to-inosine editing), which could predict the clinical outcome and immunotherapeutic efficacy of BCa, thus conferring a promising orientation for BCa predictive, preventive, and personalized medicine (PPPM/3PM).
Methods
Unsupervised clustering was employed to categorize BCa into different RNA modification patterns on the basis of gene expression profiles of 34 RNA modification “writers”. The RNA modification “writers” score (RMS) signature composed of RNA phenotype-associated differentially expressed genes (DEGs) was established using the least absolute shrinkage and selection operator (LASSO). The prognostic power of the RMS model was evaluated using Kaplan-Meier analysis and receiver operating characteristic curves. A visualized nomogram was established for BCa risk stratification. The potential applicability of the RMS model in predicting the therapeutic responsiveness was assessed through the Genomics of Drug Sensitivity in Cancer database and multiple immunotherapy datasets.
Results
Two distinct RNA modification patterns were determined among 1410 BCa samples, showing radically varying clinical outcomes and biological characteristics. The RMS model comprising 14 RNA modification phenotype-associated prognostic DEGs was positively correlated with the unsatisfactory outcome of BCa patients in a meta-GEO training cohort (HR = 3.00, 95% CI = 2.19–4.12) and the TCGA-BLCA validation cohort (HR = 1.53, 95% CI = 1.13–2.09). The infiltration of immunosuppressive cells and the activation of EMT, angiogenesis, IL-6/JAK/STAT3 signaling were markedly enriched in RMS-high cohort. A nomogram including age, N classification and the RMS exhibited high prognostic prediction accuracy, with a concordance index of 0.745. The combination of the RMS model and conventional characteristics (TMB, TNB and PD-L1) achieved an optimal area under the curve of 0.828 in differentiating responders from non-responders to immunotherapy based on IMvigor210 cohort.
Conclusion
Our report conferred the first landscape of five forms of RNA modifications in BCa and emphasized the excellent power of the RNA modifications-related model in evaluating prognosis and immunotherapeutic efficacy. In accordance with our model, physicians can not only conduct early identification of high-risk patients to confer them with priority attention and targeted prevention, but also judge patients’ responses to immunotherapy in advance to render personalized therapy, which is conducive to the research and practice of PPPM/3PM in BCa.