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Nat Genet. 2017 Jan;49(1):65-74. doi: 10.1038/ng.3722. Epub 2016 Nov 21.

Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.

Author information

1
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
2
The Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
3
Biotech Research and Innovation Centre (BRIC), Copenhagen, Denmark.
4
Department of Translational Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.
5
Division of Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
8
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.
9
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.
12
Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
13
Institute of Pathology, Jena University Hospital, Jena, Germany.
14
General Surgery, Heidelberg University Clinics, Heidelberg, Germany.
15
Department of Cardiothoracic Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
16
Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
17
Institute of Pathology, Technical University Munich, Munich, Germany.
18
Department of Pathology, University Hospital Cologne, Cologne, Germany.
19
German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
20
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
21
European Molecular Biology Laboratory (EMBL), Cell Biology Unit, Heidelberg, Germany.
22
European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, UK.

Abstract

Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.

PMID:
27869826
PMCID:
PMC5791882
DOI:
10.1038/ng.3722
[Indexed for MEDLINE]
Free PMC Article

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