title: Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
abstract: Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.
authors.affiliation: Departments of Surgery and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Farshad
authors.initials: F
authors.lastname: Farshidfar
authors.affiliation: Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.affiliation: University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Newton
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Shih
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
authors.forename: A Gordon
authors.initials: AG
authors.lastname: Robertson
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hinoue
authors.affiliation: Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Gibb
authors.affiliation: Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Covington
authors.affiliation: Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chia-Chin
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Eve
authors.initials: E
authors.lastname: Shinbrot
authors.affiliation: Blueprint Medicines, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.affiliation: Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Apurva
authors.initials: A
authors.lastname: Hegde
authors.affiliation: Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Ju Dong
authors.initials: JD
authors.lastname: Yang
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA.
authors.forename: Ed
authors.initials: E
authors.lastname: Reznik
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Sadeghi
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL 35294, USA; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Akinyemi I
authors.initials: AI
authors.lastname: Ojesina
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Hess
authors.affiliation: Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: J Todd
authors.initials: JT
authors.lastname: Auman
authors.affiliation: USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Suhn K
authors.initials: SK
authors.lastname: Rhie
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
authors.forename: Reanne
authors.initials: R
authors.lastname: Bowlby
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA.
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.affiliation: Departments of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Josh M
authors.initials: JM
authors.lastname: Stuart
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rehan
authors.initials: R
authors.lastname: Akbani
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cherniack
authors.affiliation: Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Taofic
authors.initials: T
authors.lastname: Mounajjed
authors.affiliation: Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wai Chin
authors.initials: WC
authors.lastname: Foo
authors.affiliation: Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.affiliation: National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Autumn J
authors.initials: AJ
authors.lastname: McRee
authors.affiliation: Departments of Surgery and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Oliver F
authors.initials: OF
authors.lastname: Bathe
authors.affiliation: Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: jesper.andersen@bric.ku.dk.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Andersen
authors.affiliation: Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bardeesy.nabeel@mgh.harvard.edu.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: roberts.lewis@mayo.edu.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lkwong@mdanderson.org.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics*; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D014157:Transcription Factors; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: ARID1A; DNA methylation; IDH; RNA sequencing; TCGA; cholangiocarcinoma; integrative genomics; lncRNAs; multi-omics; whole exome