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 language | English |
|---|---|
| Pages (from-to) | 2230-2247 |
| Number of pages | 18 |
| Journal | Cancer Discovery |
| Volume | 11 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sept 2021 |
Bibliographical note
Funding Information:We thank the High-Throughput Sequencing Unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ) for providing excellent services regarding all sequencing experiments. We are grateful to Norman Mack, Laura Sieber, Britta Statz, Monika Mauermann, Lukas Schmitt, and Tatjana Wedig, Department of Pediatric Neu-rooncology, German Cancer Research Center, and Laura Doerner, Lisa Kreinbihl, Jochen Meyer, Lea Hofmann and Moritz Schalles, Department of Neuropathology, Heidelberg University Hospital, for excellent technical assistance. This study was generously supported by the Ein Kiwi gegen Krebs-foundation. We thank the German Childhood Cancer Foundation for funding (?Molecular Neuropathology 2.0?Increasing diagnostic accuracy in paediatric neurooncology?; DKS 2015.01). Furthermore, this work was supported by fellowships of German Academic Exchange Service (DAAD; to T. Zheng), the Mildred-Scheel doctoral program of the German Cancer Aid (to D.R. Ghasemi), the German Academic Scholarship Foundation (to D.R. Ghasemi), the Hertie Network of Excellence in Clinical Neuroscience (to P. Sievers), the Else Kr?ner Excellence Program of the Else Kr?ner-Fresenius Stiftung (EKFS; to F. Sahm), a grant from the Japan Agency for Medical Research and Development, AMED (JP20ck0106534h0001), Fund for the Promotion of Joint Inter-national Research (19K24687, JSPS; to D. Kawauchi), and the Collaborative Ependymoma Research Network (CERN) fellowship (to K.W. Pajtler). U. Sch?ller was supported by the Gert und Susanna Mayer Stif-tung and the F?rdergemeinschaft Kinderkrebszentrum Hamburg. Part of the study was funded by the National Institute for Health Research to UCLH Biomedical research center (BRC399/NS/RB/101410). S. Brand-ner was also supported by the Department of Health?s NIHR Biomedical Research Centre?s funding scheme. A. Korshunov is supported by the Helmholtz Association Research Grant (Germany). M. Ryzhova is supported by the RSF Research Grant No. 18-45-06012. The methylation profiling at NYU is in part supported by the Friedberg Charitable Foundation and the Making Headway Foundation grants (to M. Snuderl). We thank Maximilian Harkotte, Department of Psychology, Eberhard Karls University T?bingen, for advice regarding data analysis and Niklas Fre-und, MRC Laboratory of Molecular Biology and Cambridge University, for fruitful discussions. We are grateful to all patients and their families for taking part in this study.
Funding Information:
D.R. Ghasemi reports other support from German Cancer Aid and German Academic Scholarship Foundation during the conduct of the study. P. Benites Goncalves da Silva reports personal fees from CNPq— Conselho Nacional de Desenvolvimento Científico e Tecnológico outside the submitted work. G. Fleischhack reports grants from German Children Cancer Foundation during the conduct of the study; grants from German Children Cancer Foundation and other support from Novartis outside the submitted work. S. Rutkowski reports grants from German Children’s Cancer Foundation during the conduct of the study; personal fees from BMS and Roche outside the submitted work. V. Ramaswamy reports personal fees from AstraZeneca outside the submitted work. D. Capper reports a patent for DNA methylation–based method for classifying tumor species pending. T. Milde reports grants from BioMed Valley Discoveries outside the submitted work. R.J. Gilbertson reports grants from Cancer Research UK, Brain Tumour Charity and NCI during the conduct of the study. S.M. Pfister reports grants from Eli Lilly, Roche, Pfizer, Bayer, epo, Charles River, and PharmaMar outside the submitted work. F. Sahm reports grants and other support from Illumina, Agilent, AbbVie, and Medac outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
We thank the High-Throughput Sequencing Unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ) for providing excellent services regarding all sequencing experiments. We are grateful to Norman Mack, Laura Sieber, Britta Statz, Monika Mauer-mann, Lukas Schmitt, and Tatjana Wedig, Department of Pediatric Neu-rooncology, German Cancer Research Center, and Laura Doerner, Lisa Kreinbihl, Jochen Meyer, Lea Hofmann and Moritz Schalles, Department of Neuropathology, Heidelberg University Hospital, for excellent technical assistance. This study was generously supported by the Ein Kiwi gegen Krebs-foundation. We thank the German Childhood Cancer Foundation for funding (“Molecular Neuropathology 2.0–Increasing diagnostic accuracy in paediatric neurooncology”; DKS 2015.01). Furthermore, this work was supported by fellowships of German Academic Exchange Service (DAAD; to T. Zheng), the Mildred-Scheel doctoral program of the German Cancer Aid (to D.R. Ghasemi), the German Academic Scholarship Foundation (to D.R. Ghasemi), the Hertie Network of Excellence in Clinical Neuroscience (to P. Sievers), the Else Kröner Excellence Program of the Else Kröner-Fresenius Stiftung (EKFS; to F. Sahm), a grant from the Japan Agency for Medical Research and Development, AMED (JP20ck0106534h0001), Fund for the Promotion of Joint International Research (19K24687, JSPS; to D. Kawauchi), and the Collaborative Ependymoma Research Network (CERN) fellowship (to K.W. Pajtler). U. Schüller was supported by the Gert und Susanna Mayer Stif-tung and the Fördergemeinschaft Kinderkrebszentrum Hamburg. Part of the study was funded by the National Institute for Health Research to UCLH Biomedical research center (BRC399/NS/RB/101410). S. Brand-ner was also supported by the Department of Health’s NIHR Biomedical Research Centre’s funding scheme. A. Korshunov is supported by the Helmholtz Association Research Grant (Germany). M. Ryzhova is supported by the RSF Research Grant No. 18-45-06012. The methylation profiling at NYU is in part supported by the Friedberg Charitable Foundation and the Making Headway Foundation grants (to M. Snuderl). We thank Maximilian Harkotte, Department of Psychology, Eberhard Karls University Tübingen, for advice regarding data analysis and Niklas Freund, MRC Laboratory of Molecular Biology and Cambridge University, for fruitful discussions. We are grateful to all patients and their families for taking part in this study.
Publisher Copyright:
© 2021 American Association for Cancer Research.
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