M. M. Streppel, E. A. Montgomery and A. Maitra Pages 58 - 68 ( 11 )
Barrett’s esophagus (BE) is a premalignant condition in the esophagus, with a rising incidence rate among Caucasians, and an established risk factor for the subsequent progression to esophageal adenocarcinoma (EAC). In contrast to the stratified squamous epithelium that normally lines the distal esophagus, BE is characterized by columnar epithelium that to some extent resembles the mucosa of the lower intestinal tract. The mechanism of intestinalization of the esophagus is still uncertain. For many years, it was postulated that either abnormal differentiation of resident progenitor cells in the esophagus, or transdifferentiation of mature esophageal keratinocytes provoked by reflux-induced genetic alterations, resulted in the BE phenotype. However, more recent studies suggest that indigenous progenitor cells at the gastro-esophageal junction might, under unfavorable conditions such as TP63 loss or an activated inflammatory response, migrate to the esophagus and initiate columnar cell differentiation. In this review, we discuss the competing theories of the origins of BE, as well as the role of developmental signaling pathways such as Notch, Hedgehog, and Wnt/β-catenin signaling that have been implicated in the molecular pathogenesis of BE and EAC. Additionally, we provide an overview of the mutational landscapes of BE and EAC, derived from the results of recently published next generation sequencing (NGS) studies. Future research should elucidate whether NGS on endoscopic mucosal biopsies can help in identifying BE patients at highest risk for EAC development, and whether some of the prevalent mutations are “actionable”, leading to improvements in current therapeutic strategies for BE and EAC.
Barrett’s esophagus, esophageal adenocarcinoma, hedgehog, next generation sequencing, notch, origin, wnt.
, , Department of Pathology, Division of Gastrointestinal and Liver Pathology, Johns Hopkins School of Medicine, Sidney Kimmel David Koch Cancer Research Building, 1550 Orleans Street, Room 341, Baltimore, Maryland 21231, USA.