Clonal transitions and phenotypic evolution in Barrett's oesophagus

Background & AimsBarrett 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. MethodsWe 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 HE 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. 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. ConclusionsWe 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. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=154 HEIGHT=200 SRC="FIGDIR/small/21252894v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1ff4a0org.highwire.dtl.DTLVardef@1f53784org.highwire.dtl.DTLVardef@fc973org.highwire.dtl.DTLVardef@729d0d_HPS_FORMAT_FIGEXP M_FIG C_FIG A) The cardiac gland as the basic unit of Barrett esophagus that can evolve into phenotypes that adapt to the esophageal microenvironment. B) Phenotypic diversity of non-dysplastic glands is associated with the presence of dysplasia or cancer in patients with BE.