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Nat Genet. 2014 Aug;46(8):837-843. doi: 10.1038/ng.3013. Epub 2014 Jun 22.

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.

Author information

1
MRC Cancer Unit, University of Cambridge, Cambridge, UK.
2
CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
3
Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
4
Cancer Sciences Division, University of Southampton, Southampton, UK.
5
Fluidigm Corporation, South San Francisco, California, USA.
6
Oesophago-Gastric Unit, Addenbrooke's Hospital, Cambridge, UK.
7
Oxford ComLab, University of Oxford, UK.
8
British Columbia Cancer Research Centre, Cancer Agency Research Centre, Canada.
9
Department of Pathology, University of Cambridge, Cambridge, UK.
#
Contributed equally

Abstract

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n=66) and high-grade dysplasia (HGD; n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

PMID:
24952744
PMCID:
PMC4116294
DOI:
10.1038/ng.3013
[Indexed for MEDLINE]
Free PMC Article

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