Intrinsic Cellular Susceptibility to Barrett’s Esophagus in Adults Born with Esophageal Atresia

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Abstract

The prevalence of Barrett’s esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux. Given the overlap between genes and pathways involved in foregut and BE development, we hypothesized that EA patients have an intrinsic predisposition to develop BE. Transcriptomes of Esophageal biopsies of EA patients with BE (n = 19, EA/BE); EA patients without BE (n = 44, EA-only) and BE patients without EA (n = 10, BE-only) were compared by RNA expression profiling. Subsequently, we simulated a reflux episode by exposing fibroblasts of 3 EA patients and 3 controls to acidic conditions. Transcriptome responses were compared to the differential expressed transcripts in the biopsies. Predisposing single nucleotide polymorphisms, associated with BE, were slightly increased in EA/BE versus BE-only patients. RNA expression profiling and pathway enrichment analysis revealed differences in retinoic acid metabolism and downstream signaling pathways and inflammatory, stress response and oncological processes. There was a similar effect on retinoic acid signaling and immune response in EA patients upon acid exposure. These results indicate that epithelial tissue homeostasis in EA patients is more prone to acidic disturbances.

Original languageEnglish
Article number513
JournalCancers
Volume14
Issue number3
DOIs
Publication statusPublished - 20 Jan 2022

Bibliographical note

Funding Information:
Acknowledgments: In memoriam of our friend and colleague, we would like to dedicate this manuscript to Robert M.W. Hofstra. His insightful guidance during this project was always appreciated. This research project is supported by the European Reference Network for rare Inherited and Congenital Anomalies (ERNICA, https://ern-ernica.eu/, accessed on 24 November 2021). Furthermore, we thank all patients who participated in the Biobank Esophageal Atresia and Biobank Barrett for their cooperation. We thank Floor Vergouwe, Ruben van der Bogt and Anne-Fleur van Hal for their help collecting the patient material for the biobanks. We thank Hedwika Nastiti for her help with the sequencing work. We thank Jonathan Windster for his help with the graphic artwork.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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