Evolution of Barrett’s Esophagus through space and time at single-crypt and whole-biopsy levels [Batch 7 of 7]

ABSTRACT: Barrett’s esophagus is a condition in which the squamous epithelium of the esophagus is replaced with a metaplastic crypt-structured epithelium and progresses to esophageal adenocarcinoma in a minority of cases. It is an ideal human system in which to study the evolutionary dynamics of progression. Previous results suggested that there is a low mutation rate in Barrett’s, based on measures of whole biopsies. However, it was unclear if this was due to a low mutation rate in crypts or a high mutation rate in crypts with a low clonal expansion rate. We used phylogenetic analyses to study copy-number alterations in the epithelium of 67 whole biopsies and 291 single crypts from those biopsies in 8 individuals with Barrett’s esophagus, including 4 cancer progressors. While crypts contained some private mutations, the mutation load and inferred mutation rate in crypts were similar to those in whole biopsies; the latter thus being a reasonable substrate for studies of the mutational process. Diversity between biopsies and within biopsies were strongly correlated. Mutations were more frequent near the gastro-esophageal junction and genomic instability appeared to precede genome doubling, leading to clonal expansions in two cases. This suggests that progression is driven by rare, carcinogenic alterations of large effect, rather than the gradual accumulation of many alterations of small effect, and explains why most patients with Barrett’s esophagus do not progress to esophageal adenocarcinoma. These results shed light on the evolutionary dynamics underlying neoplastic progression in Barrett’s esophagus. Batch 7 of 7

ORGANISM(S): Homo sapiens

PROVIDER: GSE99429 | GEO | 2018/01/30

REPOSITORIES: GEO