title: Paired exome analysis of Barrett's esophagus and adenocarcinoma.
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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Stachler
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Shouyong
authors.initials: S
authors.lastname: Peng
authors.affiliation: University of Washington, Seattle, Washington, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Agoston T
authors.initials: AT
authors.lastname: Agoston
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Odze
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Davison
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Katie S
authors.initials: KS
authors.lastname: Nason
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Ignaty
authors.initials: I
authors.lastname: Leshchiner
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Seepo
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Daysha
authors.initials: D
authors.lastname: Ferrer-Torres
authors.affiliation: Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jules
authors.initials: J
authors.lastname: Lin
authors.affiliation: Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chang
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: David G
authors.identifier: http://orcid.org/0000-0002-2662-9507
authors.initials: DG
authors.lastname: Beer
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.|Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.|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.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Eli and Edythe L. Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D001471:Barrett Esophagus / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004252:DNA Mutational Analysis; D004938:Esophageal Neoplasms / Q000235:genetics*; D059472:Exome; D005784:Gene Amplification; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017354:Point Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human