期刊
NATURE GENETICS
卷 49, 期 1, 页码 65-74出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3722
关键词
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资金
- Network of Excellence - European Commission [260791]
- German Ministry for Science and Education (BMBF) [01KU1505F, 01ZX1303A, 01ZX1406]
- European Research Council (ERC) Starting Grant [336045]
- Danish Medical Research Council [DFF-4183-00233]
- DFG [KFO 227/BA 4806/1-2, KFO 227/GL286/1-1]
- Baden-Wurttemberg Stiftung [P-LS-ASII/33]
- iMed (Helmholtz Initiative on Personalized Oncology)
- EU [TRANSCAN-2 ERA-NET]
- German Cancer Aid (Colon-Resist-Net)
- SNSF Early Postdoc Mobility Fellowship [P2ELP3_155365]
- EMBO Long-Term Fellowship [ALTF 755-2014]
- German Cancer Research Center
- Heidelberg School of Oncology
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.
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