Cell Reports (Mar 2017)
Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles
- Farshad Farshidfar,
- Siyuan Zheng,
- Marie-Claude Gingras,
- Yulia Newton,
- Juliann Shih,
- A. Gordon Robertson,
- Toshinori Hinoue,
- Katherine A. Hoadley,
- Ewan A. Gibb,
- Jason Roszik,
- Kyle R. Covington,
- Chia-Chin Wu,
- Eve Shinbrot,
- Nicolas Stransky,
- Apurva Hegde,
- Ju Dong Yang,
- Ed Reznik,
- Sara Sadeghi,
- Chandra Sekhar Pedamallu,
- Akinyemi I. Ojesina,
- Julian M. Hess,
- J. Todd Auman,
- Suhn K. Rhie,
- Reanne Bowlby,
- Mitesh J. Borad,
- Andrew X. Zhu,
- Josh M. Stuart,
- Chris Sander,
- Rehan Akbani,
- Andrew D. Cherniack,
- Vikram Deshpande,
- Taofic Mounajjed,
- Wai Chin Foo,
- Michael S. Torbenson,
- David E. Kleiner,
- Peter W. Laird,
- David A. Wheeler,
- Autumn J. McRee,
- Oliver F. Bathe,
- Jesper B. Andersen,
- Nabeel Bardeesy,
- Lewis R. Roberts,
- Lawrence N. Kwong
Affiliations
- Farshad Farshidfar
- Departments of Surgery and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Siyuan Zheng
- 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
- Marie-Claude Gingras
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Yulia Newton
- University of California Santa Cruz, Santa Cruz, CA 95064, USA
- Juliann Shih
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- A. Gordon Robertson
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
- Toshinori Hinoue
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA
- Katherine A. Hoadley
- Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Ewan A. Gibb
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
- Jason Roszik
- 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
- Kyle R. Covington
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Chia-Chin Wu
- 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
- Eve Shinbrot
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Nicolas Stransky
- Blueprint Medicines, 38 Sidney Street, Cambridge, MA 02139, USA
- Apurva Hegde
- 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
- Ju Dong Yang
- Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- Ed Reznik
- Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA
- Sara Sadeghi
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
- Chandra Sekhar Pedamallu
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- Akinyemi I. Ojesina
- University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Julian M. Hess
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- J. Todd Auman
- Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Suhn K. Rhie
- USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
- Reanne Bowlby
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
- Mitesh J. Borad
- Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA
- Andrew X. Zhu
- Departments of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Josh M. Stuart
- University of California Santa Cruz, Santa Cruz, CA 95064, USA
- Chris Sander
- Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA
- Rehan Akbani
- 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
- Andrew D. Cherniack
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- Vikram Deshpande
- Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Taofic Mounajjed
- Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- Wai Chin Foo
- 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
- Michael S. Torbenson
- Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- David E. Kleiner
- National Cancer Institute, Bethesda, MD 20892, USA
- Peter W. Laird
- Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA
- David A. Wheeler
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Autumn J. McRee
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Oliver F. Bathe
- Departments of Surgery and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
- Jesper B. Andersen
- Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
- Nabeel Bardeesy
- Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Lewis R. Roberts
- Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- Lawrence N. Kwong
- 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
- DOI
- https://doi.org/10.1016/j.celrep.2017.02.033
- Journal volume & issue
-
Vol. 18,
no. 11
pp. 2780 – 2794
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.
Keywords
- TCGA
- cholangiocarcinoma
- multi-omics
- integrative genomics
- DNA methylation
- RNA sequencing
- lncRNAs
- IDH
- whole exome
- ARID1A
