title: Mutational spectrum of Barrett's stem cells suggests paths to initiation of a precancerous lesion.
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.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Computational &Systems Biology, Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
authors.forename: Denis
authors.initials: D
authors.lastname: Bertrand
authors.affiliation: Department of Computational &Systems Biology, Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
authors.forename: Florian
authors.initials: F
authors.lastname: Kern
authors.affiliation: Department of Computational &Systems Biology, Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Duleba
authors.affiliation: Department of Pathology, National University Heath System, Singapore 119228, Singapore.
authors.forename: Supriya
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Computational &Systems Biology, Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.affiliation: Department of Computational &Systems Biology, Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
authors.forename: Yuanyu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Lane H
authors.initials: LH
authors.lastname: Wilson
authors.affiliation: Digestive Health Center, Maine Medical Center, South Portland, Maine 04102, USA.
authors.forename: Hagen
authors.initials: H
authors.lastname: Blaszyk
authors.affiliation: Digestive Health Center, Maine Medical Center, South Portland, Maine 04102, USA.
authors.forename: Daniil
authors.initials: D
authors.lastname: Rolshud
authors.affiliation: Department of Pathology, National University Heath System, Singapore 119228, Singapore.
authors.forename: Ming
authors.initials: M
authors.lastname: Teh
authors.affiliation: Department of Computational &Systems Biology, Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
authors.affiliation: Ocata Therapeutics, Inc., Marlborough, Massachusetts 01752, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.affiliation: Department of Computational &Systems Biology, Genome Institute of Singapore, A-STAR, Singapore 138672, Singapore.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Nagarajan
authors.affiliation: Department of Medicine, National University of Singapore, Singapore 119228, Singapore.
authors.forename: Khek Yu
authors.initials: KY
authors.lastname: Ho
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.|Department of Microbiology, National University of Singapore, Singapore 119228, Singapore.|MultiClonal Therapeutics, Inc., Farmington, Connecticut 06030, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: McKeon
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.|MultiClonal Therapeutics, Inc., Farmington, Connecticut 06030, USA.|Center for Stem Cell &Regenerative Medicine, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.|Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School, Houston, Texas 77030, USA.
authors.forename: Wa
authors.initials: W
authors.lastname: Xian
mesh_terms: D000818:Animals; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured