Abstract 5741: Characterizing isoform switching events in esophageal adenocarcinoma

Abstract

Abstract Esophageal adenocarcinoma (EAC), the major subtype of esophageal cancer in the US, is characterized by increasing incidence rates and high mortality due to ineffective screening, late-stage diagnosis, and poor treatment efficacy. The only known precursor to EAC is Barrett’s Esophagus (BE), but the precise mechanisms and molecular events leading to disease progression are still being unraveled. In recent years, analysis of TCGA data revealed that isoform switching events with predicted functional consequences are common in many cancers, but the characterization of switching events in esophageal adenocarcinoma (EAC) is lacking. Next-generation sequencing was utilized to detect levels of RNA transcripts and specific isoforms in 66 treatment naïve esophageal tissues from 41 patients. Tissues ranged from premalignant Barrett’s esophagus (BE), BE with low or high-grade dysplasia (LGD or HGD) to EAC. Samples were stratified by histopathology, p53 mutation status, and significant isoform switching events with predicted functional consequences, followed by enrichment analysis. Barrett’s with high-grade dysplasia increased risk for EAC progression. Comparing BE with LGD and BE with HGD, isoform switching events were identified in 75 genes including KRAS, APC, RNF-128 and WRAP53. Stratification based on p53 status increased the number of significant isoform switches to 135 suggesting switching events impact cellular functions based on tissue histopathology, as well as p53 status. Analysis of isoforms agnostic to mutant p53, exclusive to mutant p53, and shared between the two groups revealed unique signatures including demethylation, lipid and retinoic acid metabolism, and glucuronidation, respectively. About 25% of isoform switching events were identified without significant alteration of gene-level expression. Importantly, two p53-interacting isoforms, RNF128 and WRAP53, were significantly linked to patient survival. Analysis of global isoform switching consequences and alternative splicing events also revealed significant changes in the fraction of coding transcripts, complete open-reading-frames, signal peptides, alternative 5’ donor sites, and alternative transcription start sites. Thus, analysis of isoform switching events may provide new insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC treatment or prevention. Citation Format: Yun Zhang, Katherine M. Weh, Connor L. Howard, Jean-Jack Riethoven, Jennifer L. Clarke, Kiran H. Lagisetty, Jules Lin, Rishindra M. Reddy, Andrew C. Chang, David G. Beer, Laura A. Kresty. Characterizing isoform switching events in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5741.