Comprehensive Analysis of Alternative Splicing in Gastric Cancer Identifies Epithelial-Mesenchymal Transition Subtypes Associated with Survival

Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer have not been comprehensively characterized. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa, identifying and experi...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2022-02, Vol.82 (4), p.543-555
Main Authors: Jun, Yukyung, Suh, Yun-Suhk, Park, SungHee, Lee, Jieun, Kim, Jong-Il, Lee, Sanghyuk, Lee, Wan-Ping, Anczuków, Olga, Yang, Han-Kwang, Lee, Charles
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Alternative Splicing
Cell Line, Tumor
Cluster Analysis
Epithelial-Mesenchymal Transition - genetics
Female
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic
Genome and Epigenome
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Reverse Transcriptase Polymerase Chain Reaction
RNA Splicing Factors - genetics
RNA-Binding Proteins - genetics
RNA-Seq - methods
Stomach Neoplasms - classification
Stomach Neoplasms - genetics
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Summary:Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer have not been comprehensively characterized. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa, identifying and experimentally validating eight splicing events that can classify all gastric cancers into three subtypes: epithelial-splicing (EpiS), mesenchymal-splicing (MesS), and hybrid-splicing. These subtypes were associated with distinct molecular signatures and epithelial-mesenchymal transition markers. Subtype-specific splicing events were enriched in motifs for splicing factors RBM24 and ESRP1, which were upregulated in MesS and EpiS tumors, respectively. A simple classifier based only on RNA levels of RBM24 and ESRP1, which can be readily implemented in the clinic, was sufficient to distinguish gastric cancer subtypes and predict patient survival in multiple independent patient cohorts. Overall, this study provides insights into alternative splicing in gastric cancer and the potential clinical utility of splicing-based patient classification. This study presents a comprehensive analysis of alternative splicing in the context of patient classification, molecular mechanisms, and prognosis in gastric cancer.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-21-2117