Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion-positive supratentorial ependymomas
Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
April 20, 2021
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| In: |
Cancer discovery
Year: 2021, Jahrgang: 11, Heft: 9, Pages: 2230-2247 |
| ISSN: | 2159-8290 |
| DOI: | 10.1158/2159-8290.CD-20-0963 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/2159-8290.CD-20-0963 Verlag, lizenzpflichtig, Volltext: https://cancerdiscovery.aacrjournals.org/content/11/9/2230 
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| Verfasserangaben: | Tuyu Zheng, David R. Ghasemi, Konstantin Okonechnikov, Andrey Korshunov, Martin Sill, Kendra K. Maass, Patricia Benites Goncalves da Silva, Marina Ryzhova, Johannes Gojo, Damian Stichel, Amir Arabzade, Robert Kupp, Julia Benzel, Shinichiro Taya, Toma Adachi, Ryo Shiraishi, Nicolas U. Gerber, Dominik Sturm, Jonas Ecker, Philipp Sievers, Florian Selt, Rebecca Chapman, Christine Haberler, Dominique Figarella-Branger, Guido Reifenberger, Gudrun Fleischhack, Stefan Rutkowski, Andrew M. Donson, Vijay Ramaswamy, David Capper, David W. Ellison, Christel C. Herold-Mende, Ulrich Schüller, Sebastian Brandner, Pablo Hernáiz Driever, Johan M. Kros, Matija Snuderl, Till Milde, Richard G. Grundy, Mikio Hoshino, Stephen C. Mack, Richard J. Gilbertson, David T.W. Jones, Marcel Kool, Andreas von Deimling, Stefan M. Pfister, Felix Sahm, Daisuke Kawauchi, and Kristian W. Pajtler |
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| 245 | 1 | 0 | |a Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion-positive supratentorial ependymomas |c Tuyu Zheng, David R. Ghasemi, Konstantin Okonechnikov, Andrey Korshunov, Martin Sill, Kendra K. Maass, Patricia Benites Goncalves da Silva, Marina Ryzhova, Johannes Gojo, Damian Stichel, Amir Arabzade, Robert Kupp, Julia Benzel, Shinichiro Taya, Toma Adachi, Ryo Shiraishi, Nicolas U. Gerber, Dominik Sturm, Jonas Ecker, Philipp Sievers, Florian Selt, Rebecca Chapman, Christine Haberler, Dominique Figarella-Branger, Guido Reifenberger, Gudrun Fleischhack, Stefan Rutkowski, Andrew M. Donson, Vijay Ramaswamy, David Capper, David W. Ellison, Christel C. Herold-Mende, Ulrich Schüller, Sebastian Brandner, Pablo Hernáiz Driever, Johan M. Kros, Matija Snuderl, Till Milde, Richard G. Grundy, Mikio Hoshino, Stephen C. Mack, Richard J. Gilbertson, David T.W. Jones, Marcel Kool, Andreas von Deimling, Stefan M. Pfister, Felix Sahm, Daisuke Kawauchi, and Kristian W. Pajtler |
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| 520 | |a Molecular groups of supratentorial ependymomas comprise tumors with ZFTA-RELA or YAP1-involving fusions and fusion-negative subependymoma. However, occasionally supratentorial ependymomas cannot be readily assigned to any of these groups due to lack of detection of a typical fusion and/or ambiguous DNA methylation-based classification. An unbiased approach with a cohort of unprecedented size revealed distinct methylation clusters composed of tumors with ependymal but also various other histologic features containing alternative translocations that shared ZFTA as a partner gene. Somatic overexpression of ZFTA-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation in vivo, and cross-species comparative analyses identified GLI2 as a key downstream regulator of tumorigenesis in all tumors. Targeting GLI2 with arsenic trioxide caused extended survival of tumor-bearing animals, indicating a potential therapeutic vulnerability in ZFTA fusion-positive tumors. - Significance: ZFTA-RELA fusions are a hallmark feature of supratentorial ependymoma. We find that ZFTA acts as a partner for alternative transcriptional activators in oncogenic fusions of supratentorial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by ZFTA fusion-positive tumors, such as GLI2.This article is highlighted in the In This Issue feature, p. 2113 | ||
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