Abstract
Background & AimsBarrett’s 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.MethodsUsing immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome.ResultsWe identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0–2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time.ConclusionsWe showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE.
Highlights
Barrett esophagus (BE) is the only known precursor condition of esophageal adenocarcinoma (EA) and is characterized by the metaplastic replacement of the normal squamous epithelium of the distal esophagus with a columnar epithelial phenotype that frequently containsJournal Pre-proof intestinal metaplasia (IM)1
We revealed a common ancestor between parietal cell-containing, mature gastric and goblet cell-containing, intestinal gland phenotypes
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 postesophagectomy BE patients suggesting that diversity develops over-time
Summary
Barrett esophagus (BE) is the only known precursor condition of esophageal adenocarcinoma (EA) and is characterized by the metaplastic replacement of the normal squamous epithelium of the distal esophagus with a columnar epithelial phenotype that frequently containsJournal Pre-proof intestinal metaplasia (IM). We have previously shown that glands that do not contain goblet cells can clonally expand, accumulate oncogenic TP53 mutations and be the source of EA7. This finding highlights an important lack of understanding of the evolution of the BE epithelial phenotype. The significance of the evolution of gland phenotype in BE has not been fully appreciated This is an important omission when we consider that all current diagnoses are entirely based on histopathological analysis and that natural selection acts fundamentally on phenotype not genotype. We do not fundamentally understand the phenotypic evolution of Barrett’s esophagus, nor do we fully understand the distribution of gland phenotype diversity and if this associated with progression.
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