Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation

Marie-Claude Gingras; Kyle R Covington; David K Chang; Lawrence A Donehower; Anthony J Gill; Michael M Ittmann; Chad J Creighton; Amber L Johns; Eve Shinbrot; Ninad Dewal; William E Fisher; Australian Pancreatic Cancer Genome Initiative; Christian Pilarsky; Robert Grützmann; Michael J Overman; Nigel B Jamieson; George Van Buren 2nd; Jennifer Drummond; Kimberly Walker; Oliver A Hampton; Liu Xi; Donna M Muzny; Harsha Doddapaneni; Sandra L Lee; Michelle Bellair; Jianhong Hu; Yi Han; Huyen H Dinh; Mike Dahdouli; Jaswinder S Samra; Peter Bailey; Nicola Waddell; John V Pearson; Ivon Harliwong; Huamin Wang; Daniela Aust; Karin A Oien; Ralph H Hruban; Sally E Hodges; Amy McElhany; Charupong Saengboonmee; Fraser R Duthie; Sean M Grimmond; Andrew V Biankin; David A Wheeler; Richard A Gibbs

doi:10.1016/j.celrep.2015.12.005

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation

Cell Rep. 2016 Feb 2;14(4):907-919. doi: 10.1016/j.celrep.2015.12.005. Epub 2016 Jan 21.

Authors

Marie-Claude Gingras¹, Kyle R Covington², David K Chang³, Lawrence A Donehower⁴, Anthony J Gill⁵, Michael M Ittmann⁶, Chad J Creighton⁷, Amber L Johns⁸, Eve Shinbrot², Ninad Dewal², William E Fisher⁹; Australian Pancreatic Cancer Genome Initiative; Christian Pilarsky¹⁰, Robert Grützmann¹¹, Michael J Overman¹², Nigel B Jamieson¹³, George Van Buren 2nd⁹, Jennifer Drummond², Kimberly Walker², Oliver A Hampton², Liu Xi², Donna M Muzny², Harsha Doddapaneni², Sandra L Lee², Michelle Bellair², Jianhong Hu², Yi Han², Huyen H Dinh², Mike Dahdouli², Jaswinder S Samra¹⁴, Peter Bailey¹⁵, Nicola Waddell¹⁶, John V Pearson¹⁶, Ivon Harliwong¹⁷, Huamin Wang¹⁸, Daniela Aust¹⁹, Karin A Oien²⁰, Ralph H Hruban²¹, Sally E Hodges²², Amy McElhany²², Charupong Saengboonmee²³, Fraser R Duthie²⁰, Sean M Grimmond²⁴, Andrew V Biankin³, David A Wheeler²⁵, Richard A Gibbs²

Affiliations

¹ 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: [email protected].
² Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
⁹ 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.
¹⁰ Department of Surgery, TU Dresden, 01307 Dresden, Germany.
¹¹ Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
¹² Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ 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.
¹⁴ Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.
¹⁵ Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK.
¹⁶ 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.
¹⁷ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
¹⁸ Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁹ Department of Pathology, TU Dresden, 01307 Dresden, Germany.
²⁰ 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.
²¹ Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
²² 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.
²³ 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.
²⁴ 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.
²⁵ 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / metabolism
Ampulla of Vater / pathology
Base Sequence
DNA-Binding Proteins / genetics*
Duodenal Neoplasms / genetics*
Duodenal Neoplasms / metabolism
Genomic Instability
Humans
Microsatellite Repeats
Molecular Sequence Data
Mutation*
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / metabolism
Proto-Oncogene Proteins c-ets / genetics*
Transcription Factors / genetics*
Wnt Signaling Pathway*

Substances

DNA-Binding Proteins
ELF3 protein, human
Proto-Oncogene Proteins c-ets
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding