| Literature DB >> 27869826 |
Joachim Weischenfeldt1,2,3, Taronish Dubash4,5, Alexandros P Drainas1, Balca R Mardin1, Yuanyuan Chen6, Adrian M Stütz1, Sebastian M Waszak1, Graziella Bosco7, Ann Rita Halvorsen8, Benjamin Raeder1, Theocharis Efthymiopoulos1, Serap Erkek1,9, Christine Siegl4,5, Hermann Brenner10, Odd Terje Brustugun8,11, Sebastian M Dieter4,5, Paul A Northcott12, Iver Petersen13, Stefan M Pfister9, Martin Schneider14, Steinar K Solberg15, Erik Thunissen16, Wilko Weichert17,18,19, Thomas Zichner1, Roman Thomas7,18, Martin Peifer7,20, Aslaug Helland8,11, Claudia R Ball4,5,19, Martin Jechlinger21, Rocio Sotillo6, Hanno Glimm4,5,19, Jan O Korbel1,22.
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.Entities:
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Year: 2016 PMID： 27869826 PMCID： PMC5791882 DOI： 10.1038/ng.3722
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330