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000119229 0247_ $$2doi$$a10.1038/ng.3722
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000119229 0247_ $$2ISSN$$a1061-4036
000119229 0247_ $$2ISSN$$a1546-1718
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000119229 1001_ $$aWeischenfeldt, Joachim$$b0
000119229 245__ $$aPan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.
000119229 260__ $$aNew York, NY$$bNature America$$c2017
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000119229 520__ $$aExtensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.
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000119229 7001_ $$0P:(DE-He78)fd92a33f8a02f962db52bf8daa1b1dbf$$aDubash, Taronish Dorab$$b1$$udkfz
000119229 7001_ $$00000-0001-9081-9850$$aDrainas, Alexandros P$$b2
000119229 7001_ $$aMardin, Balca R$$b3
000119229 7001_ $$0P:(DE-HGF)0$$aChen, Yuanyuan$$b4
000119229 7001_ $$aStütz, Adrian M$$b5
000119229 7001_ $$00000-0003-3042-9521$$aWaszak, Sebastian M$$b6
000119229 7001_ $$aBosco, Graziella$$b7
000119229 7001_ $$aHalvorsen, Ann Rita$$b8
000119229 7001_ $$00000-0002-9494-8884$$aRaeder, Benjamin$$b9
000119229 7001_ $$aEfthymiopoulos, Theocharis$$b10
000119229 7001_ $$0P:(DE-He78)df8660bc5aba525f7fb6dba4aac15c1c$$aErkek, Serap$$b11
000119229 7001_ $$0P:(DE-He78)be98d27bcd782f4e5961b646107dc14b$$aSiegl, Christine$$b12
000119229 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b13
000119229 7001_ $$aBrustugun, Odd Terje$$b14
000119229 7001_ $$0P:(DE-He78)34c336827b750ba10a020fd62ec4664f$$aDieter, Sebastian$$b15
000119229 7001_ $$aNorthcott, Paul A$$b16
000119229 7001_ $$aPetersen, Iver$$b17
000119229 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b18
000119229 7001_ $$aSchneider, Martin$$b19
000119229 7001_ $$aSolberg, Steinar K$$b20
000119229 7001_ $$aThunissen, Erik$$b21
000119229 7001_ $$aWeichert, Wilko$$b22
000119229 7001_ $$aZichner, Thomas$$b23
000119229 7001_ $$aThomas, Roman$$b24
000119229 7001_ $$aPeifer, Martin$$b25
000119229 7001_ $$aHelland, Aslaug$$b26
000119229 7001_ $$0P:(DE-He78)7a10ea1b9b2872da9f375002c44ddfce$$aBall, Claudia$$b27
000119229 7001_ $$aJechlinger, Martin$$b28
000119229 7001_ $$0P:(DE-HGF)0$$aSotillo, Rocio$$b29
000119229 7001_ $$0P:(DE-He78)157277fe62f07df1732f9d126a51d1b9$$aGlimm, Hanno$$b30
000119229 7001_ $$00000-0002-2798-3794$$aKorbel, Jan O$$b31
000119229 773__ $$0PERI:(DE-600)1494946-5$$a10.1038/ng.3722$$gVol. 49, no. 1, p. 65 - 74$$n1$$p65 - 74$$tNature genetics$$v49$$x1546-1718$$y2017
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