Comprehensive analysis of alternative splicing in gastric cancer identifies epithelial-mesenchymal transition subtypes associated with survival.

Yukyung Jun, The Jackson Laboratory
Yun-Suhk Suh
SungHee Park, The Jackson Laboratory
Jieun Lee
Jong-Il Kim
Sanghyuk Lee
Wan-Ping Lee, The Jackson Laboratory
Olga Anczuków, The Jackson Laboratory
Han-Kwang Yang
Charles Lee, The Jackson Laboratory

Abstract

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, mesenchymal-splicing, 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 mesenchymal-splicing and epithelial-splicing 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.