Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma

Zhongru Fan; Zhe Zhang; Chiyuan Piao; Zhuona Liu; Zeshu Wang; Chuize Kong

doi:10.3389/fonc.2021.626858

Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma

Front Oncol. 2021 Mar 26:11:626858. doi: 10.3389/fonc.2021.626858. eCollection 2021.

Authors

Zhongru Fan¹, Zhe Zhang¹, Chiyuan Piao¹, Zhuona Liu¹, Zeshu Wang¹, Chuize Kong¹

Affiliation

¹ Department of Urology, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China.

Abstract

Background: Alternative splicing (AS) is an indispensable post-transcriptional modification applied during the maturation of mRNA, and AS defects have been associated with many cancers. This study was designed to thoroughly analyze AS events in bladder urothelial carcinoma (BLCA) at the genome-wide level.

Methods: We adopted a gap analysis to screen for significant differential AS events (DASEs) associated with BLCA. DASEs with prognostic value for OS and the disease-free interval (DFI) were identified by Cox analysis. In addition, a differential AS network and AS clusters were identified using unsupervised cluster analysis. We examined differences in the sensitivity to chemotherapy and immunotherapy between BLCA patients with high and low overall survival (OS) risk.

Results: An extensive number of DASEs (296) were found to be clinically relevant in BLCA. A prognosis model was established based prognostic value of OS and DFI. CUGBP elav-like family member 2 (CELF2) was identified as a hub splicing factor for AS networks. We also identified AS clusters associated with OS using unsupervised cluster analysis, and we predicted that the effects of cisplatin and gemcitabine chemotherapy would be different between high- and low-risk groups based on OS prognosis.

Conclusion: We completed a comprehensive analysis of AS events in BLCA at the genome-wide level. The present findings revealed that DASEs and splicing factors tended to impact BLCA patient survival and sensitivity to chemotherapy drugs, which may provide novel prospects for BLCA therapies.

Keywords: alternative splicing (AS); bladder urothelial carcinoma (BLCA); immuno/chemotherapies; prognosis signature; regulatory network; splicing factor.