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Cell Rep. 2017 Mar 14;18(11):2780-2794. doi: 10.1016/j.celrep.2017.02.033.

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

Collaborators (193)

Akbani R, Allotey LK, Ally A, Alvaro D, Andersen JB, Appelbaum EL, Arora A, Auman JT, Balasundaram M, Balu S, Bardeesy N, Bathe OF, Baylin SB, Beroukhim R, Berrios M, Bodenheimer T, Boice L, Bootwalla MS, Borad MJ, Bowen J, Bowlby R, Bragazzi MC, Brooks D, Cardinale V, Carlsen R, Carpino G, Carvalho AL, Chaiteerakij R, Chandan VC, Cherniack AD, Chin L, Cho J, Choe G, Chuah E, Chudamani S, Cibulskis C, Cordes MG, Covington KR, Crain D, Curley E, De Rose AM, Defreitas T, Demchok JA, Deshpande V, Dhalla N, Ding L, Evason K, Farshidfar F, Felau I, Ferguson ML, Foo WC, Franchitto A, Frazer S, Fronick CC, Fulton LA, Fulton RS, Gabriel SB, Gardner J, Gastier-Foster JM, Gaudio E, Gehlenborg N, Genovese G, Gerken M, Getz G, Giama NH, Gibbs RA, Gingras MC, Giuliante F, Grazi GL, Hayes DN, Hegde AM, Heiman DI, Hess JM, Hinoue T, Hoadley KA, Holbrook A, Holt RA, Hoyle AP, Huang M, Hutter CM, Jefferys SR, Jones SJM, Jones CD, Kasaian K, Kelley RK, Kim J, Kleiner DE, Kocher JA, Kwong LN, Lai PH, Laird PW, Lawrence MS, Leraas KM, Lichtenberg TM, Lin P, Liu W, Liu J, Lolla L, Lu Y, Ma Y, Mallery D, Mardis ER, Marra MA, Matsushita MM, Mayo M, McLellan MD, McRee AJ, Meier S, Meng S, Meyerson M, Mieczkowski PA, Miller CA, Mills GB, Moore RA, Morris S, Mose LE, Moser CD, Mounajjed T, Mungall AJ, Mungall K, Murray BA, Naresh R, Newton Y, Noble MS, O'Brien DR, Ojesina AI, Parker JS, Patel TC, Paulauskis J, Pedamallu CS, Penny R, Perou CM, Perou AH, Pihl T, Radenbaugh AJ, Ramirez NC, Rathmell WK, Reznik E, Rhie SK, Roach J, Roberts LR, Robertson AG, Sadeghi S, Saksena G, Sander C, Schein JE, Schmidt HK, Schumacher SE, Shelton C, Shelton T, Shen R, Sheth M, Shi Y, Shih J, Shinbrot E, Shroff R, Simons JV, Sipahimalani P, Skelly T, Sofia HJ, Soloway MG, Stoppler H, Stransky N, Stuart J, Sun Q, Tam A, Tan D, Tarnuzzer R, Thiessen N, Thorne LB, Torbenson MS, Van Den Berg DJ, Veluvolu U, Verhaak RGW, Voet D, Wan Y, Wang Z, Weinstein JN, Weisenberger DJ, Wheeler DA, Wilson RK, Wise L, Wong T, Wu CC, Wu Y, Xi L, Yang JD, Yang L, Zenklusen JC, Zhang H, Zhang JJ, Zheng S, Zmuda E.

Author information

1
Departments of Surgery and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
2
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.
3
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
4
University of California Santa Cruz, Santa Cruz, CA 95064, USA.
5
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.
6
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
7
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
8
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.
9
Blueprint Medicines, 38 Sidney Street, Cambridge, MA 02139, USA.
10
Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
11
Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA.
12
University of Alabama at Birmingham, Birmingham, AL 35294, USA; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
13
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
14
Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
15
USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
16
Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA.
17
Departments of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
18
Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
19
National Cancer Institute, Bethesda, MD 20892, USA.
20
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
21
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: jesper.andersen@bric.ku.dk.
22
Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bardeesy.nabeel@mgh.harvard.edu.
23
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.
24
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.

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:

ARID1A; DNA methylation; IDH; RNA sequencing; TCGA; cholangiocarcinoma; integrative genomics; lncRNAs; multi-omics; whole exome

PMID:
28297679
PMCID:
PMC5493145
DOI:
10.1016/j.celrep.2017.02.033
[Indexed for MEDLINE]
Free PMC Article

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