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Nat Genet. 2015 Sep;47(9):1047-55. doi: 10.1038/ng.3343. Epub 2015 Jul 20.

Paired exome analysis of Barrett's esophagus and adenocarcinoma.

Author information

1
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
3
Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
4
University of Washington, Seattle, Washington, USA.
5
University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
6
Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan, USA.
7
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
8
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
9
Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Broad Institute of Harvard and MIT, Harvard Medical School, Boston, Massachusetts, USA.
10
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
11
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

Abstract

Barrett's esophagus is thought to progress to esophageal adenocarcinoma (EAC) through a stepwise progression with loss of CDKN2A followed by TP53 inactivation and aneuploidy. Here we present whole-exome sequencing from 25 pairs of EAC and Barrett's esophagus and from 5 patients whose Barrett's esophagus and tumor were extensively sampled. Our analysis showed that oncogene amplification typically occurred as a late event and that TP53 mutations often occurred early in Barrett's esophagus progression, including in non-dysplastic epithelium. Reanalysis of additional EAC exome data showed that the majority (62.5%) of EACs emerged following genome doubling and that tumors with genomic doubling had different patterns of genomic alterations, with more frequent oncogenic amplification and less frequent inactivation of tumor suppressors, including CDKN2A. These data suggest that many EACs emerge not through the gradual accumulation of tumor-suppressor alterations but rather through a more direct path whereby a TP53-mutant cell undergoes genome doubling, followed by the acquisition of oncogenic amplifications.

Comment in

PMID:
26192918
PMCID:
PMC4552571
DOI:
10.1038/ng.3343
[Indexed for MEDLINE]
Free PMC Article

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