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

Joachim 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 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

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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.

Original language	English
Pages (from-to)	65-74
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	1
DOIs	https://doi.org/10.1038/ng.3722
State	Published - 1 Jan 2017

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Weischenfeldt, J., 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

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

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.",

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

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Weischenfeldt, J, 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, vol. 49, no. 1, pp. 65-74. https://doi.org/10.1038/ng.3722

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AU - Weischenfeldt, Joachim

AU - Dubash, Taronish

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.

PY - 2017/1/1

Y1 - 2017/1/1

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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DO - 10.1038/ng.3722

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JO - Nature Genetics

JF - Nature Genetics

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ER -

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

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