title: Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.
abstract: Through exomic sequencing of 32 intrahepatic cholangiocarcinomas, we discovered frequent inactivating mutations in multiple chromatin-remodeling genes (including BAP1, ARID1A and PBRM1), and mutation in one of these genes occurred in almost half of the carcinomas sequenced. We also identified frequent mutations at previously reported hotspots in the IDH1 and IDH2 genes encoding metabolic enzymes in intrahepatic cholangiocarcinomas. In contrast, TP53 was the most frequently altered gene in a series of nine gallbladder carcinomas. These discoveries highlight the key role of dysregulated chromatin remodeling in intrahepatic cholangiocarcinomas.
authors.affiliation: The Ludwig Center, Johns Hopkins University, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA.|Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.|Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Pawlik
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Florin M
authors.initials: FM
authors.lastname: Selaru
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Mirte M
authors.initials: MM
authors.lastname: Streppel
authors.affiliation: Department of Surgery, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Lucas
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Noushin
authors.initials: N
authors.lastname: Niknafs
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Violeta Beleva
authors.initials: VB
authors.lastname: Guthrie
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.affiliation: Department of Pathology, University Medical Center, Utrecht, The Netherlands.
authors.forename: G Johan A
authors.initials: GJA
authors.lastname: Offerhaus
authors.affiliation: Department of Pathology, Universidad de La Frontera, Temuco, Chile.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Roa
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.affiliation: Dan Setlacec Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Irinel
authors.initials: I
authors.lastname: Popescu
authors.affiliation: Dan Setlacec Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Sorin T
authors.initials: ST
authors.lastname: Alexandrescu
authors.affiliation: Dan Setlacec Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
authors.forename: Simona
authors.initials: S
authors.lastname: Dima
authors.affiliation: Applied Research on Cancer Network, Miriam Cherubini Research Centre, University of Verona, Verona, Italy.|Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Applied Research on Cancer Network, Miriam Cherubini Research Centre, University of Verona, Verona, Italy.|Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Simbolo
authors.affiliation: Applied Research on Cancer Network, Miriam Cherubini Research Centre, University of Verona, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mafficini
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Capelli
authors.affiliation: Applied Research on Cancer Network, Miriam Cherubini Research Centre, University of Verona, Verona, Italy.|Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Rita T
authors.initials: RT
authors.lastname: Lawlor
authors.affiliation: Department of Surgery, University of Verona, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruzzenente
authors.affiliation: Department of Surgery, University of Verona, Verona, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Guglielmi
authors.affiliation: Department of Medicine, Medical Oncology Unit, University of Verona, Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Medical Oncology Unit 1, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Applied Research on Cancer Network, Miriam Cherubini Research Centre, University of Verona, Verona, Italy.|Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: William
authors.initials: W
authors.lastname: Jarnagin
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Klimstra
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.affiliation: The Ludwig Center, Johns Hopkins University, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA.|Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.|Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: The Ludwig Center, Johns Hopkins University, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA.|Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: The Ludwig Center, Johns Hopkins University, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA.|Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: The Ludwig Center, Johns Hopkins University, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, Maryland, USA.|Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
mesh_terms: D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D059472:Exome / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C112476:ARID1A protein, human; C400134:BAP1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase