Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion– positive supratentorial ependymomas

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 SieversFlorian 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, Kristian W. Pajtler

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)

Abstract

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 unbi-ased 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 compara-tive 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 supraten-torial tumors with various histologic characteristics. Establishing representative mouse models, we identify potential therapeutic targets shared by ZFTA fusion–positive tumors, such as GLI2.

Original languageEnglish
Pages (from-to)2230-2247
Number of pages18
JournalCancer Discovery
Volume11
Issue number9
DOIs
Publication statusPublished - Sep 2021

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