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

Full text not available from this repository.

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:
CreatorsEmailORCIDORCID Put Code
Weischenfeldt, JoachimUNSPECIFIEDorcid.org/0000-0002-3917-5524UNSPECIFIED
Dubash, TaronishUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Drainas, Alexandros P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mardin, Balca R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, YuanyuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stuetz, Adrian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waszak, Sebastian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bosco, GraziellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halvorsen, Ann RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raeder, BenjaminUNSPECIFIEDorcid.org/0000-0002-9494-8884UNSPECIFIED
Efthymiopoulos, TheocharisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erkek, SerapUNSPECIFIEDorcid.org/0000-0003-4439-5203UNSPECIFIED
Siegl, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brenner, HermannUNSPECIFIEDorcid.org/0000-0002-6129-1572UNSPECIFIED
Brustugun, Odd TerjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dieter, Sebastian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Northcott, Paul A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petersen, IverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfister, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solberg, Steinar K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thunissen, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weichert, WilkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zichner, ThomasUNSPECIFIEDorcid.org/0000-0001-9848-7598UNSPECIFIED
Thomas, RomanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Helland, AslaugUNSPECIFIEDorcid.org/0000-0002-5520-0275UNSPECIFIED
Ball, Claudia R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jechlinger, MartinUNSPECIFIEDorcid.org/0000-0002-3710-4466UNSPECIFIED
Sotillo, RocioUNSPECIFIEDorcid.org/0000-0002-0855-7917UNSPECIFIED
Glimm, HannoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korbel, Jan O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
SUPER-ENHANCERS; CHROMATIN DOMAINS; CELL IDENTITY; PAIRED-END; LANDSCAPE; MUTATIONS; GENOME; REARRANGEMENTS; EXPRESSION; PROMOTESMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/24381

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item