title: Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation.
abstract: The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: mgingras@bcm.edu.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, NSW 2170, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Chang
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.affiliation: The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, TX 77030, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Johns
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Eve
authors.initials: E
authors.lastname: Shinbrot
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ninad
authors.initials: N
authors.lastname: Dewal
authors.affiliation: Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Fisher
authors.affiliation: Department of Surgery, TU Dresden, 01307 Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
authors.affiliation: Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; Academic Unit of Surgery, Institute of Cancer Sciences, Glasgow Royal Infirmary, Level 2, New Lister Building, University of Glasgow, Glasgow G31 2ER, UK.
authors.forename: Nigel B
authors.initials: NB
authors.lastname: Jamieson
authors.affiliation: Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: George
authors.initials: G
authors.lastname: Van Buren
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Drummond
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Walker
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Hampton
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Xi
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Harsha
authors.initials: H
authors.lastname: Doddapaneni
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Lee
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bellair
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Huyen H
authors.initials: HH
authors.lastname: Dinh
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Dahdouli
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.
authors.forename: Jaswinder S
authors.initials: JS
authors.lastname: Samra
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bailey
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
authors.forename: Ivon
authors.initials: I
authors.lastname: Harliwong
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology, TU Dresden, 01307 Dresden, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Aust
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Department of Pathology, Southern General Hospital, Greater Glasgow and Clyde NHS, Glasgow G51 4TF, UK.
authors.forename: Karin A
authors.initials: KA
authors.lastname: Oien
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Hodges
authors.affiliation: Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: McElhany
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Charupong
authors.initials: C
authors.lastname: Saengboonmee
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Department of Pathology, Southern General Hospital, Greater Glasgow and Clyde NHS, Glasgow G51 4TF, UK.
authors.forename: Fraser R
authors.initials: FR
authors.lastname: Duthie
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, NSW 2170, Australia.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wheeler@bcm.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D014670:Ampulla of Vater / Q000473:pathology; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D004379:Duodenal Neoplasms / Q000235:genetics* / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D060449:Wnt Signaling Pathway
chemical_list: D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors