Understanding the Epigenetic Landscape of Barrett's Esophagus and Esophageal Cancer: A Review of Current Findings, Caveats and Future Directions.

Esophageal cancer (OC) is currently the eighth most common form of cancer worldwide with a 5-year survival rate of 10%-20%, with the primary risk factor of esophageal adenocarcinoma (OAC) being the development of Barrett's Esophagus (BO). Despite its clinical significance, the molecular pathogenesis underlying both BO and OC is not well understood. In recent years, epigenetic dysregulation, particularly aberrant DNA methylation, has emerged as a critical area of investigation, given its potential utility in the identification of diagnostic, prognostic, and therapeutic biomarkers. This review examines the evolving epigenetic landscape of esophageal cancer, including a focus on its origins in BO with a particular emphasis on DNA methylation, the most extensively researched epigenetic mechanism. Key DNA methylation-associated alterations involved in OAC and OSCC initiation and progression are discussed, alongside their potential clinical application as biomarkers for early detection, prognosis, and risk stratification in BO populations. Furthermore, the role of these epigenetically regulated genes in the disruption of Wnt signaling and cell cycle control pathways implicated in esophageal carcinogenesis is explored. The review concludes by outlining future research directions, current challenges, and the promise of epigenetic studies in advancing our understanding of OC pathogenesis and improving patient outcomes.