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Nat Commun. 2016 Jan 19;7:10380. doi: 10.1038/ncomms10380.

Mutational spectrum of Barrett's stem cells suggests paths to initiation of a precancerous lesion.

Author information

1
Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
2
Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.
3
Department of Computational &Systems Biology, Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
4
Department of Pathology, National University Heath System, Singapore 119228, Singapore.
5
Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
6
Digestive Health Center, Maine Medical Center, South Portland, Maine 04102, USA.
7
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
8
Ocata Therapeutics, Inc., Marlborough, Massachusetts 01752, USA.
9
Department of Medicine, National University of Singapore, Singapore 119228, Singapore.
10
Department of Microbiology, National University of Singapore, Singapore 119228, Singapore.
11
MultiClonal Therapeutics, Inc., Farmington, Connecticut 06030, USA.
12
Center for Stem Cell &Regenerative Medicine, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
13
Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas 77030, USA.

Abstract

The precancerous lesion known as Barrett's oesophagus can evolve to oesophageal adenocarcinoma in decades-long processes of regenerative growth. Here we report the isolation and propagation of distinct, patient-matched stem cells of Barrett's, gastric and oesophageal epithelia that yield divergent tumour types following in vitro transformation and xenografting. Genomic analyses reveal a broad mutational spectrum unique to Barrett's stem cells that likely reflects their risk for oncogenesis. Remarkably, 25% of cases show no cancer-related genomic changes, suggesting that Barrett's initiates without driver mutations. Most cases, however, sustain patterns of deletions almost identical to adenocarcinoma though tumour-associated gene amplifications were absent. Notably, those suspected of low-grade dysplasia have p53 mutations or undergo amplifications of proto-oncogenes and receptor tyrosine kinases, implicating these events in lethal transitions. Our findings suggest paths for the initiation and progression of Barrett's and define a discrete stem cell underlying its regenerative growth whose eradication could prevent oesophageal adenocarcinoma.

PMID:
26783136
PMCID:
PMC4735693
DOI:
10.1038/ncomms10380
[Indexed for MEDLINE]
Free PMC Article

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