A multi-omics analysis and clinical relevance of regualted cell death in bladder cancer

Abstract

Abstract The dysfunction of regulated cell death (RCD) could cause human diseases such as cancer, neurodegeneration, autoimmune diseases, and infectious diseases. Recent studies have indicated that RCD has closely functional interaction. Our study aimed to explore the cross-talk, genetic alteration, functions, mechanism, and cluster relevance of the several major types of RCD, including apoptosis, ferroptosis, pyroptosis, necroptosis, autophagy-dependent cell death, in bladder cancer (BLCA). Through analyzing the public database, we found that the genes representing these five RCD types showed complex cross-talk in mRNA, protein levels, somatic mutation, and DNA copy number in BLCA. The mRNA expression of regulated cell death genes (RCDGs) was affected by DNA copy number, somatic mutation, DNA methylation, and RNA modification. Several RCDGs were essential for cell viability, and the expression of RCDGs was correlated with radiotherapeutic sensitivity and IC50 of chemotherapy drugs. Based on the expression of RCDGs, the BLCA patients were divided into two clusters. We found multiple immune-related pathways significantly enriched in cluster1/cluster2. In addition, the patients' prognosis, immune therapy response, and drug sensitivity in these two clusters were significantly different. Through the comparison between the RCD clusters and consensus cluster, we found that RCD cluster1 mainly correlated with the basal squamous cluster, and the RCD cluster2 mainly correlated with the luminal cluster. Through the weighted gene co-expression network analysis (WGCNA), we identified the high correlation RCDGs with cluster1/cluster2. We found that most cluster1-RCDGs were correlated with poor prognosis for patients, and most prognosis-protection genes correlated with cluster2. Besides, the expression of these prognosis-related RCDGs showed different distribution patterns in basal/luminal subtypes. In summary, our study conducted a comprehensive analysis of RCDGs in BLCA, which provided the foundation for subsequent experiments and therapeutic options.