title: Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma.
abstract: Esophageal cancer ranks sixth in cancer death. To explore its genetic origins, we conducted exomic sequencing on 11 esophageal adenocarcinomas (EAC) and 12 esophageal squamous cell carcinomas (ESCC) from the United States. Interestingly, inactivating mutations of NOTCH1 were identified in 21% of ESCCs but not in EACs. There was a substantial disparity in the spectrum of mutations, with more indels in ESCCs, A:T>C:G transversions in EACs, and C:G>G:C transversions in ESCCs (P < 0.0001). Notably, NOTCH1 mutations were more frequent in North American ESCCs (11 of 53 cases) than in ESCCs from China (1 of 48 cases). A parallel analysis found that most mutations in EACs were already present in matched Barrett esophagus. These discoveries highlight key genetic differences between EACs and ESCCs and between American and Chinese ESCCs, and suggest that NOTCH1 is a tumor suppressor gene in the esophagus. Finally, we provide a genetic basis for the evolution of EACs from Barrett esophagus.
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institutions, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. nagrawal@jhmi.edu
authors.forename: Nishant
authors.initials: N
authors.lastname: Agrawal
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.forename: Chetan
authors.initials: C
authors.lastname: Bettegowda
authors.forename: Susan M
authors.initials: SM
authors.lastname: Hutfless
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Stefan
authors.initials: S
authors.lastname: David
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.forename: William S
authors.initials: WS
authors.lastname: Twaddell
authors.forename: Nyan L
authors.initials: NL
authors.lastname: Latt
authors.forename: Eun J
authors.initials: EJ
authors.lastname: Shin
authors.forename: Li-Dong
authors.initials: LD
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Wancai
authors.initials: W
authors.lastname: Yang
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002681:China; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059472:Exome; D005843:Geography; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009154:Mutation; D009656:North America; D051881:Receptor, Notch1 / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics; D017422:Sequence Analysis, DNA; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C499374:NOTCH3 protein, human; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53