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

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Summary

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.

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The Genotype-Tissue Expression (GTEx) project.

John M. Lonsdale, Jeffrey Thomas, Mike Salvatore … (2014)

Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.

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Mutational heterogeneity in cancer and the search for new cancer genes

Michael S Lawrence, Petar Stojanov, Paz Polak … (2013)

Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.

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Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

Timothy Ley, Christopher Miller, Li Ding … (2013)

Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).

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Author and article information

Journal

Journal ID (nlm-journal-id): 101573691

Journal ID (pubmed-jr-id): 39703

Journal ID (nlm-ta): Cell Rep

Journal ID (iso-abbrev): Cell Rep

Title: Cell reports

ISSN (Electronic): 2211-1247

Publication date Nihms-submitted: 14 April 2017

Publication date (Print): 14 March 2017

Publication date PMC-release: 30 June 2017

Volume: 18

Issue: 11

Pages: 2780-2794

Affiliations

[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

[6 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA

[7 ]Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada

[8 ]Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA

[9 ]Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

[10 ]Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

[11 ]Blueprint Medicines, 38 Sidney Street, Cambridge, MA 02139, USA

[12 ]Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

[13 ]Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA

[14 ]University of Alabama at Birmingham, Birmingham, AL 35294, USA

[15 ]HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA

[16 ]USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA

[17 ]Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA

[18 ]Departments of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

[19 ]Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

[20 ]National Cancer Institute, Bethesda, MD 20892, USA

[21 ]Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark

Author notes

[22]

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[23]

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Article

Manuscript ID: NIHMS866722

DOI: 10.1016/j.celrep.2017.02.033

PMC ID: 5493145

PubMed ID: 28297679

SO-VID: e32f97d5-eb45-4196-bdab-59c4ff72333c

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This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/).

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

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Claudins

Most cited references 55

The Genotype-Tissue Expression (GTEx) project.

Mutational heterogeneity in cancer and the search for new cancer genes

Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

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