Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking

Joachim Lütken Weischenfeldt; Taronish Dubash; Alexandros P Drainas; Balca R Mardin; Yuanyuan Chen; Adrian M Stütz; Sebastian M Waszak; Graziella Bosco; Ann Rita Halvorsen; Benjamin Raeder; Theocharis Efthymiopoulos; Serap Erkek; Christine Siegl; Hermann Brenner; Odd Terje Brustugun; Sebastian M Dieter; Paul A Northcott; Iver Petersen; Stefan M Pfister; Martin Schneider; Steinar K Solberg; Erik Thunissen; Wilko Weichert; Thomas Zichner; Roman Thomas; Martin Peifer; Aslaug Helland; Claudia R Ball; Martin Jechlinger; Rocio Sotillo; Hanno Glimm; Jan O Korbel

doi:10.1038/ng.3722

Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking

Joachim Lütken Weischenfeldt, Taronish Dubash, Alexandros P Drainas, Balca R Mardin, Yuanyuan Chen, Adrian M Stütz, Sebastian M Waszak, Graziella Bosco, Ann Rita Halvorsen, Benjamin Raeder, Theocharis Efthymiopoulos, Serap Erkek, Christine Siegl, Hermann Brenner, Odd Terje Brustugun, Sebastian M Dieter, Paul A Northcott, Iver Petersen, Stefan M Pfister, Martin SchneiderSteinar K Solberg, Erik Thunissen, Wilko Weichert, Thomas Zichner, Roman Thomas, Martin Peifer, Aslaug Helland, Claudia R Ball, Martin Jechlinger, Rocio Sotillo, Hanno Glimm, Jan O Korbel

151 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	49
Udgave nummer	1
Sider (fra-til)	65-74
Antal sider	10
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3722
Status	Udgivet - 1 jan. 2017

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10.1038/ng.3722

http://europepmc.org/articles/pmc5791882?pdf=renderLicens: Andet

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Weischenfeldt, J. L., Dubash, T., Drainas, A. P., Mardin, B. R., Chen, Y., Stütz, A. M., Waszak, S. M., Bosco, G., Halvorsen, A. R., Raeder, B., Efthymiopoulos, T., Erkek, S., Siegl, C., Brenner, H., Brustugun, O. T., Dieter, S. M., Northcott, P. A., Petersen, I., Pfister, S. M., ... Korbel, J. O. (2017). Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nature Genetics, 49(1), 65-74. https://doi.org/10.1038/ng.3722

Weischenfeldt, JL, Dubash, T, Drainas, AP, Mardin, BR, Chen, Y, Stütz, AM, Waszak, SM, Bosco, G, Halvorsen, AR, Raeder, B, Efthymiopoulos, T, Erkek, S, Siegl, C, Brenner, H, Brustugun, OT, Dieter, SM, Northcott, PA, Petersen, I, Pfister, SM, Schneider, M, Solberg, SK, Thunissen, E, Weichert, W, Zichner, T, Thomas, R, Peifer, M, Helland, A, Ball, CR, Jechlinger, M, Sotillo, R, Glimm, H & Korbel, JO 2017, 'Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking', Nature Genetics, bind 49, nr. 1, s. 65-74. https://doi.org/10.1038/ng.3722

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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.",

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AU - Weischenfeldt, Joachim Lütken

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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 M

AU - Northcott, Paul A

AU - Petersen, Iver

AU - Pfister, Stefan M

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 R

AU - Jechlinger, Martin

AU - Sotillo, Rocio

AU - Glimm, Hanno

AU - Korbel, Jan O

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N2 - 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.

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.

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Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking

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