Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma

Nat Genet. 2015 Sep;47(9):1038-1046. doi: 10.1038/ng.3357. Epub 2015 Jul 20.

Abstract

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barrett's esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett's epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Aged
  • Barrett Esophagus / genetics*
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • Disease Progression
  • Esophageal Neoplasms / genetics*
  • Female
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide

Supplementary concepts

  • Adenocarcinoma Of Esophagus