There is no doubt that chronic gastro-esophageal reflux disease (GERD) increases the risk of esophageal adenocarcinoma (EAC) by several fold (OR=6.4, CI=4.6 to 9.1), and some relationships between reflux disease-mediated inflammation and oncogenic processes have been explored; however, the precise interconnections between the immune response and genomic instabilities underlying these pathological processes are only now emerging. Furthermore, the precise cell of origin of the pre-cancerous stages associated with EAC development, Barrett’s esophagus (BE), be it cardia resident or embryonic remnant, may shape our interpretation of the likely immune drivers. This review integrates the current collective knowledge of the immunology underlying EAC development and outlines a framework connecting pro-inflammatory pathways- such as those mediated by IL1β, TNFα, LIF, IL6, STAT3, NF-κB, COX2 and TGFβ-with oncogenic pathways in the GERD-BE-EAC cancer sequence. Further defining these immune and molecular “railroads” may reveal a map of the routes taken by gastro-esophageal cells on their journey toward EAC tumour phylogeny. The selective pressures, applied by this immune-induced journey, likely impact the phenotype and genotype of the resulting oncogenic destination and further exploration of lesser defined immune drivers may be useful in future individualized therapies or enhanced selective application of recent immune-driven therapeutics.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

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