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Characterizing isoform switching events in esophageal adenocarcinoma

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-naïv...

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Autores principales: Zhang, Yun, Weh, Katherine M., Howard, Connor L., Riethoven, Jean-Jack, Clarke, Jennifer L., Lagisetty, Kiran H., Lin, Jules, Reddy, Rishindra M., Chang, Andrew C., Beer, David G., Kresty, Laura A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437810/
https://www.ncbi.nlm.nih.gov/pubmed/36090744
http://dx.doi.org/10.1016/j.omtn.2022.08.018
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author Zhang, Yun
Weh, Katherine M.
Howard, Connor L.
Riethoven, Jean-Jack
Clarke, Jennifer L.
Lagisetty, Kiran H.
Lin, Jules
Reddy, Rishindra M.
Chang, Andrew C.
Beer, David G.
Kresty, Laura A.
author_facet Zhang, Yun
Weh, Katherine M.
Howard, Connor L.
Riethoven, Jean-Jack
Clarke, Jennifer L.
Lagisetty, Kiran H.
Lin, Jules
Reddy, Rishindra M.
Chang, Andrew C.
Beer, David G.
Kresty, Laura A.
author_sort Zhang, Yun
collection PubMed
description 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.
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spelling pubmed-94378102022-09-10 Characterizing isoform switching events in esophageal adenocarcinoma Zhang, Yun Weh, Katherine M. Howard, Connor L. Riethoven, Jean-Jack Clarke, Jennifer L. Lagisetty, Kiran H. Lin, Jules Reddy, Rishindra M. Chang, Andrew C. Beer, David G. Kresty, Laura A. Mol Ther Nucleic Acids Original Article 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. American Society of Gene & Cell Therapy 2022-08-17 /pmc/articles/PMC9437810/ /pubmed/36090744 http://dx.doi.org/10.1016/j.omtn.2022.08.018 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Zhang, Yun
Weh, Katherine M.
Howard, Connor L.
Riethoven, Jean-Jack
Clarke, Jennifer L.
Lagisetty, Kiran H.
Lin, Jules
Reddy, Rishindra M.
Chang, Andrew C.
Beer, David G.
Kresty, Laura A.
Characterizing isoform switching events in esophageal adenocarcinoma
title Characterizing isoform switching events in esophageal adenocarcinoma
title_full Characterizing isoform switching events in esophageal adenocarcinoma
title_fullStr Characterizing isoform switching events in esophageal adenocarcinoma
title_full_unstemmed Characterizing isoform switching events in esophageal adenocarcinoma
title_short Characterizing isoform switching events in esophageal adenocarcinoma
title_sort characterizing isoform switching events in esophageal adenocarcinoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9437810/
https://www.ncbi.nlm.nih.gov/pubmed/36090744
http://dx.doi.org/10.1016/j.omtn.2022.08.018
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