TY  - JOUR
AU  - Weischenfeldt, Joachim
AU  - Dubash, Taronish Dorab
AU  - Drainas, Alexandros P
AU  - Mardin, Balca R
AU  - Chen, Yuanyuan
AU  - Stütz, Adrian M
AU  - Waszak, Sebastian M
AU  - Bosco, Graziella
AU  - Halvorsen, Ann Rita
AU  - Raeder, Benjamin
AU  - Efthymiopoulos, Theocharis
AU  - Erkek, Serap
AU  - Siegl, Christine
AU  - Brenner, Hermann
AU  - Brustugun, Odd Terje
AU  - Dieter, Sebastian
AU  - Northcott, Paul A
AU  - Petersen, Iver
AU  - Pfister, Stefan
AU  - Schneider, Martin
AU  - Solberg, Steinar K
AU  - Thunissen, Erik
AU  - Weichert, Wilko
AU  - Zichner, Thomas
AU  - Thomas, Roman
AU  - Peifer, Martin
AU  - Helland, Aslaug
AU  - Ball, Claudia
AU  - Jechlinger, Martin
AU  - Sotillo, Rocio
AU  - Glimm, Hanno
AU  - Korbel, Jan O
TI  - Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.
JO  - Nature genetics
VL  - 49
IS  - 1
SN  - 1546-1718
CY  - New York, NY
PB  - Nature America
M1  - DKFZ-2017-00019
SP  - 65 - 74
PY  - 2017
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:27869826
DO  - DOI:10.1038/ng.3722
UR  - https://inrepo02.dkfz.de/record/119229
ER  -