Clonal Transitions and Phenotypic Evolution in Barrett's Esophagus

AIMS: Barrett esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change and how phenotypic diversity plays a role in progression. METHODS: Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsies from non-dysplastic BE patients and those that had progressed to dysplasia or had developed post-esophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome. RESULTS: We identified five different gland phenotypes in a cohort of 51 non-dysplastic patients where biopsies were taken at the same anatomical site (1.0-2.0 cm superior to the gastroesophageal junction. Here we observed the same number of glands with one and two phenotypes, but three phenotypes were rare. We revealed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have demonstrated a clonal relationship between cardiac-type glands, specialized and mature intestinal glands. Using the Shannon index as marker of gland diversity, we observed significantly increased phenotypic diversity in BE adjacent to dysplasia and pre-dysplasia compared to non-dysplastic BE and post-esophagectomy BE patients suggesting that diversity develops over-time. CONCLUSIONS: We showed that the range of BE phenotypes represent an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we demonstrated a common ancestry between gastric and intestinal-type glands in BE