title: Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.
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.
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.|The Finsen Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|Biotech Research and Innovation Centre (BRIC), Copenhagen, Denmark.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weischenfeldt
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Division of Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Taronish
authors.initials: T
authors.lastname: Dubash
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Alexandros P
authors.identifier: 0000-0001-9081-9850
authors.initials: AP
authors.lastname: Drainas
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Balca R
authors.initials: BR
authors.lastname: Mardin
authors.affiliation: Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Sebastian M
authors.identifier: 0000-0003-3042-9521
authors.initials: SM
authors.lastname: Waszak
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Graziella
authors.initials: G
authors.lastname: Bosco
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Ann Rita
authors.initials: AR
authors.lastname: Halvorsen
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Benjamin
authors.identifier: 0000-0002-9494-8884
authors.initials: B
authors.lastname: Raeder
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Theocharis
authors.initials: T
authors.lastname: Efthymiopoulos
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.|Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Serap
authors.initials: S
authors.lastname: Erkek
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Division of Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Siegl
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.|Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Odd Terje
authors.initials: OT
authors.lastname: Brustugun
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Division of Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Dieter
authors.affiliation: Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: Institute of Pathology, Jena University Hospital, Jena, Germany.
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: General Surgery, Heidelberg University Clinics, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
authors.forename: Steinar K
authors.initials: SK
authors.lastname: Solberg
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Thunissen
authors.affiliation: Institute of Pathology, Technical University Munich, Munich, Germany.|Department of Pathology, University Hospital Cologne, Cologne, Germany.|German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zichner
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.|Department of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.|Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Aslaug
authors.initials: A
authors.lastname: Helland
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Division of Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Ball
authors.affiliation: European Molecular Biology Laboratory (EMBL), Cell Biology Unit, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Jechlinger
authors.affiliation: Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Rocio
authors.initials: R
authors.lastname: Sotillo
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Division of Translational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.|European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Jan O
authors.identifier: 0000-0002-2798-3794
authors.initials: JO
authors.lastname: Korbel
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: C035170:IGF2 protein, human; C107686:IRS4 protein, human; D055504:Insulin Receptor Substrate Proteins; D007335:Insulin-Like Growth Factor II