Molecular characterization of Barrett's esophagus at single-cell resolution

Georg A Busslinger, Buys de Barbanson, Rurika Oka, Bas L A Weusten, Michiel de Maat, Richard van Hillegersberg, Lodewijk A A Brosens, Ruben van Boxtel, Alexander van Oudenaarden, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Barrett's esophagus (BE) is categorized, based on morphological appearance, into different stages, which correlate with the risk of developing esophageal adenocarcinoma. More advanced stages are more likely to acquire chromosomal instabilities, but stage-specific markers remain elusive. Here, we performed single-cell DNA-sequencing experiments (scDNAseq) with fresh BE biopsies. Dysplastic BE cells frequently contained chromosomal instability (CIN) regions, and these CIN cells carried mutations corresponding to the COSMIC mutational signature SBS17, which were not present in biopsy-matched chromosomally stable (CS) cells or patient-matched nondiseased control cells. CS cells were predominantly found in nondysplastic BE biopsies. The single-base substitution (SBS) signatures of all CS BE cells analyzed were indistinguishable from those of nondiseased esophageal or gastric cells. Single-cell RNA-sequencing (scRNAseq) experiments with BE biopsies identified two sets of marker genes which facilitate the distinction between columnar BE epithelium and nondysplastic/dysplastic stages. Moreover, histological validation confirmed a correlation between increased CLDN2 expression and the presence of dysplastic BE stages. Our scDNAseq and scRNAseq datasets, which are a useful resource for the community, provide insight into the mutational landscape and gene expression pattern at different stages of BE development.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number47
DOIs
Publication statusPublished - 23 Nov 2021

Keywords

  • Adenocarcinoma/genetics
  • Barrett Esophagus/diagnosis
  • Biomarkers
  • Biopsy
  • Chromosomal Instability
  • Epithelium
  • Esophagus
  • Gene Expression
  • Humans
  • Hyperplasia/pathology
  • Mutation
  • Sequence Analysis, DNA
  • Single-Cell Analysis/methods
  • Whole Exome Sequencing

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