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

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

doi:10.3389/fonc.2021.626858

Abstract

BackgroundAlternative 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.MethodsWe 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.ResultsAn 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.ConclusionWe 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.

Highlights

Bladder urothelial carcinoma (BLCA) is a common genitourinary malignancy, with an estimated 430,000 cases diagnosed annually worldwide, associated with 165,000 deaths [1]
One study identified over 4,632 survival-associated alternative splicing (AS) events (SASEs) in BLCA and indicated that the overall incidence of SASEs correlated strongly with survival [3], which indicated that AS might be a noteworthy regulatory mechanism in BLCA
A given gene could be associated with multiple types of AS events, with some genes associated with up to five or six variable splicing types (Figure 1C)

Summary

Introduction

Bladder urothelial carcinoma (BLCA) is a common genitourinary malignancy, with an estimated 430,000 cases diagnosed annually worldwide, associated with 165,000 deaths [1]. Comprehensive AS Analysis for BLCA inhibition, targeted therapies, and antibody–drug conjugates, which are used to treat muscle-invasive and advanced diseases. These treatments have been developed due to the profound understanding of the molecular biology and genetics underlying BLCA [2]. One study identified over 4,632 survival-associated alternative splicing (AS) events (SASEs) in BLCA and indicated that the overall incidence of SASEs correlated strongly with survival [3], which indicated that AS might be a noteworthy regulatory mechanism in BLCA. This study was designed to thoroughly analyze AS events in bladder urothelial carcinoma (BLCA) at the genome-wide level

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