Characterizing isoform switching events in esophageal adenocarcinoma

Authors

Yun Zhang, University of Michigan
Katherine M. Weh, University of Michigan
Connor L. Howard, University of Michigan
Jean-Jack Riethoven, University of Nebraska - LincolnFollow
Jennifer L. Clarke, University of Nebraska-LincolnFollow
Kiran H. Lagisetty, University of Michigan
Jules Lin, University of Michigan
Rishindra M. Reddy, University of Michigan
Andrew C. Chang, University of Michigan
David G. Beer, University of Michigan
Laura A. Kresty, University of MichiganFollow

Date of this Version

2022

Document Type

Article

Citation

Molecular Therapy: Nucleic Acids Vol. 29 September 2022

doi:10.1016/j.omtn.2022.08.018.

Comments

This is an open access article under the CC BY-NC-ND license

Abstract

Isoform switching events with predicted functional consequences are common in many cancers, but characterization of switching events in esophageal adenocarcinoma (EAC) is lacking. Next-generation sequencing was used to detect levels of RNA transcripts and identify specific isoforms in treatment- naïve esophageal tissues ranging from premalignant Barrett’s esophagus (BE), BE with low- or high-grade dysplasia (BE.LGD, BE.HGD), and EAC. Samples were stratified by histopathology and TP53 mutation status, identifying significant isoform switching events with predicted functional consequences. Comparing BE.LGD with BE.HGD, a histopathology linked to cancer progression, isoform switching events were identified in 75 genes including KRAS, RNF128, and WRAP53. Stratification based on TP53 status increased the number of significant isoform switches to 135, suggesting switching events affect cellular functions based on TP53 mutation and tissue histopathology. Analysis of isoforms agnostic, exclusive, and shared with mutant TP53 revealed unique signatures including demethylation, lipid and retinoic acid metabolism, and glucuronidation, respectively. Nearly half of isoform switching events were identified without significant gene-level expression changes. Importantly, two TP53-interacting isoforms, RNF128 and WRAP53, were significantly linked to patient survival. Thus, analysis of isoform switching events may provide new insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC.