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

Yusuke Yamamoto, Xia Wang, Denis Bertrand, Florian Kern, Ting Zhang, Marcin Duleba, Supriya Srivastava, Chiea Chuen Khor, Yuanyu Hu, Lane H. Wilson, Hagen Blaszyk, Daniil Rolshud, Ming Teh, Jianjun Liu, Brooke E. Howitt, Matthew Vincent, Christopher P. Crum, Niranjan Nagarajan, Khek Yu Ho, Frank McKeon () and Wa Xian ()
Additional contact information
Yusuke Yamamoto: National Cancer Center Research Institute
Xia Wang: University of Houston
Denis Bertrand: Genome Institute of Singapore, A-STAR
Florian Kern: Genome Institute of Singapore, A-STAR
Ting Zhang: Genome Institute of Singapore, A-STAR
Marcin Duleba: University of Houston
Supriya Srivastava: National University Heath System
Chiea Chuen Khor: Genome Institute of Singapore, A-STAR
Yuanyu Hu: Genome Institute of Singapore, A-STAR
Lane H. Wilson: University of Connecticut Health Center
Hagen Blaszyk: Digestive Health Center, Maine Medical Center
Daniil Rolshud: Digestive Health Center, Maine Medical Center
Ming Teh: National University Heath System
Jianjun Liu: Genome Institute of Singapore, A-STAR
Brooke E. Howitt: Brigham and Women’s Hospital
Matthew Vincent: Ocata Therapeutics, Inc.
Christopher P. Crum: Brigham and Women’s Hospital
Niranjan Nagarajan: Genome Institute of Singapore, A-STAR
Khek Yu Ho: National University of Singapore
Frank McKeon: University of Houston
Wa Xian: Brigham and Women’s Hospital

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10380

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