Universität zu Köln

Weischenfeldt, Joachim ORCID: 0000-0002-3917-5524, Dubash, Taronish, Drainas, Alexandros P., Mardin, Balca R., Chen, Yuanyuan, Stuetz, Adrian M., Waszak, Sebastian M., Bosco, Graziella, Halvorsen, Ann Rita, Raeder, Benjamin ORCID: 0000-0002-9494-8884, Efthymiopoulos, Theocharis, Erkek, Serap ORCID: 0000-0003-4439-5203, Siegl, Christine, Brenner, Hermann ORCID: 0000-0002-6129-1572, Brustugun, Odd Terje, Dieter, Sebastian M., Northcott, Paul A., Petersen, Iver, Pfister, Stefan M., Schneider, Martin, Solberg, Steinar K., Thunissen, Erik, Weichert, Wilko, Zichner, Thomas ORCID: 0000-0001-9848-7598, Thomas, Roman, Peifer, Martin ORCID: 0000-0002-5243-5503, Helland, Aslaug ORCID: 0000-0002-5520-0275, Ball, Claudia R., Jechlinger, Martin ORCID: 0000-0002-3710-4466, Sotillo, Rocio ORCID: 0000-0002-0855-7917, Glimm, Hanno and Korbel, Jan O. (2017). Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nature Genet., 49 (1). S. 65 - 75. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Weischenfeldt, Joachim UNSPECIFIED orcid.org/0000-0002-3917-5524 UNSPECIFIED Dubash, Taronish UNSPECIFIED UNSPECIFIED UNSPECIFIED Drainas, Alexandros P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mardin, Balca R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Yuanyuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Stuetz, Adrian M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Waszak, Sebastian M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bosco, Graziella UNSPECIFIED UNSPECIFIED UNSPECIFIED Halvorsen, Ann Rita UNSPECIFIED UNSPECIFIED UNSPECIFIED Raeder, Benjamin UNSPECIFIED orcid.org/0000-0002-9494-8884 UNSPECIFIED Efthymiopoulos, Theocharis UNSPECIFIED UNSPECIFIED UNSPECIFIED Erkek, Serap UNSPECIFIED orcid.org/0000-0003-4439-5203 UNSPECIFIED Siegl, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Brenner, Hermann UNSPECIFIED orcid.org/0000-0002-6129-1572 UNSPECIFIED Brustugun, Odd Terje UNSPECIFIED UNSPECIFIED UNSPECIFIED Dieter, Sebastian M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Northcott, Paul A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Petersen, Iver UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfister, Stefan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Solberg, Steinar K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thunissen, Erik UNSPECIFIED UNSPECIFIED UNSPECIFIED Weichert, Wilko UNSPECIFIED UNSPECIFIED UNSPECIFIED Zichner, Thomas UNSPECIFIED orcid.org/0000-0001-9848-7598 UNSPECIFIED Thomas, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED orcid.org/0000-0002-5243-5503 UNSPECIFIED Helland, Aslaug UNSPECIFIED orcid.org/0000-0002-5520-0275 UNSPECIFIED Ball, Claudia R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jechlinger, Martin UNSPECIFIED orcid.org/0000-0002-3710-4466 UNSPECIFIED Sotillo, Rocio UNSPECIFIED orcid.org/0000-0002-0855-7917 UNSPECIFIED Glimm, Hanno UNSPECIFIED UNSPECIFIED UNSPECIFIED Korbel, Jan O. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-243811
DOI:	10.1038/ng.3722
Journal or Publication Title:	Nature Genet.
Volume:	49
Number:	1
Page Range:	S. 65 - 75
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	NEW YORK
ISSN:	1546-1718
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SUPER-ENHANCERS; CHROMATIN DOMAINS; CELL IDENTITY; PAIRED-END; LANDSCAPE; MUTATIONS; GENOME; REARRANGEMENTS; EXPRESSION; PROMOTES Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24381