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  1. Mairi H McLean, Education editor

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Basic science

Genetic progression from Barrett's oesophagus to adenocarcinoma

▸ Stachler MD, Taylor-Weiner A, Peng S, et al. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nat Genet 2015;47:1047–55.

While most patients with Barrett's oesophagus never progress to cancer, understanding the evolutionary processes in those that are at higher cancer risk and predicting their response to therapy is crucial. Here, the authors demonstrate with exome sequencing that patients with non-dysplastic Barrett's tissue surprisingly show a mutation rate comparable with prostate, breast and colon cancers. Furthermore, the mutation rate appeared similar to Barrett's dysplasia and adenocarcinoma, suggesting that most mutations (particularly in TP53) occur early in the neoplastic progression. In contrast, genomic alterations (amplifications and deletions) were a later event, primarily occurring at the point of initiation of adenocarcinoma. Two groups of patients were identified; those that showed a common ancestry (of varying degrees) between non-dysplastic Barrett's and those that showed none, even with increased spatial resolution through laser capture microdissection. This could be explained by random sampling, leading to missed clones that led to the development of cancer and polyclones within the Barrett's lesion is a possibility. It appears that there are two genetic pathways to Barrett's adenocarcinoma. While TP53 mutations appear early in the majority of Barrett's adenocarcinoma cases, there is a clear divide between cases according to the presence of whole genome doubling (WGD). Cases that demonstrate WGD have significantly less tumour suppressor gene mutations (excluding TP53 and perhaps P16). Cases with WGD show amplifications in cell cycle regulators and transcription factors, and these may be critical events leading to invasive disease. In conclusion, this is an important paper, which demonstrates that the traditional view of the genetic progression of Barrett's oesophagus to cancer is actually two independent pathways characterised by either genome doubling and amplification of oncogenes or a gradual loss of function of several …

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  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.