Multi-omics reveals novel prognostic implication of SRC protein expression in bladder cancer and its correlation with immunotherapy response

PURPOSE: This study aims to identify potential prognostic biomarkers of bladder cancer (BCa) based on large-scale multi-omics data and investigate the role of SRC in improving predictive outcomes for BCa patients and those receiving immune checkpoint therapies (ICTs). METHODS: Large-scale multi-comic data were enrolled from the Cancer Proteome Atlas, the Cancer Genome Atlas and gene expression omnibus based on machining-learning methods. Immune infiltration, survival and other statistical analyses were implemented using R software in cancers (n = 12,452). The predictive value of SRC was performed in 81 BCa patients receiving ICT from aa validation cohort (n = 81). RESULTS: Landscape of novel candidate prognostic protein signatures of BCa patients was identified. Differential BECLIN, EGFR, PKCALPHA, ANNEXIN1, AXL and SRC expression significantly correlated with the outcomes for BCa patients from multiply cohorts (n = 906). Notably, risk score of the integrated prognosis-related proteins (IPRPs) model exhibited high diagnostic accuracy and consistent predictive ability (AUC = 0.714). Besides, we tested the clinical relevance of baseline SRC protein and mRNA expression in two independent confirmatory cohorts (n = 566) and the prognostic value in pan-cancers. Then, we found that elevated SRC expression contributed to immunosuppressive microenvironment mediated by immune checkpoint molecules of BCa and other cancers. Next, we validated SRC expression as a potential biomarker in predicting response to ICT in 81 BCa patient from FUSCC cohort, and found that expression of SRC in the baseline tumour tissues correlated with improved survival benefits, but predicts worse ICT response. CONCLUSION: This study first performed the large-scale multi-omics analysis, distinguished the IPRPs (BECLIN, EGFR, PKCALPHA, SRC, ANNEXIN1 and AXL) and revealed novel prediction model, outperforming the currently traditional prognostic indicators for anticipating BCa progression and better clinical strategies. Additionally, this study provided insight into the importance of biomarker SRC for better prognosis, which may inversely improve predictive outcomes for patients receiving ICT and enable patient selection for future clinical treatment.