Background & Aims: Barrett esophagus (BE) is a risk factor for the development of esophageal adenocarcinoma, however our understanding of how Barrett esophagus evolves is still poorly understood. We demonstrate that dynamic clonal phenotypic changes occur at the gland level, the mechanism by which these changes evolve, and how diversity may play a role in progression.
Methods: We analyzed the distribution and diversity of gland phenotype between and within BE biopsies and the background mucosa of those that had progressed to dysplasia or developed BE post-esophagectomy, using immunohistochemistry and H&E analysis. Clonal relationships between distinct gland types were determined by laser capture microdissection sequencing of the mitochondrial genome.
Results: Five different non-dysplastic gland phenotypes were identified in a cohort of 64 patients; most non-dysplastic patients showed a single gland phenotype per biopsy but some showed two or three gland types. We reveal a shared common ancestor between parietal cell-containing oxynto-cardiac glands and goblet cell-containing specialized Barrett glands through a shared somatic mtDNA mutation. We also reveal a similar relationship between specialized and cardiac-type glands, and specialized and Paneth cell-containing glands. Clonal-related distinct within gland phenotypes were also observed. The diversity of gland types was significantly increased adjacent to dysplasia compared to non-dysplastic BE and patients with post-esophagectomy BE, suggesting that gland diversity evolves in BE patients over time.
Conclusions: We have shown that the range of BE phenotypes represent an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we demonstrate common ancestry between gastric and intestinal glands in BE.
Clonal transitions and phenotypic evolution in Barrett esophagus
