Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas.
- 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 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.
- Authors:
- T Zheng, DR Ghasemi, K Okonechnikov, A Korshunov, M Sill, KK Maass, P Benites Goncalves da Silva, M Ryzhova, J Gojo, D Stichel, A Arabzade, R Kupp, J Benzel, S Taya, T Adachi, R Shiraishi, NU Gerber, D Sturm, J Ecker, P Sievers, F Selt, R Chapman, C Haberler, D Figarella-Branger, G Reifenberger, G Fleischhack, S Rutkowski, AM Donson, V Ramaswamy, D Capper, DW Ellison, CC Herold-Mende, U Schüller, S Brandner, PH Driever, JM Kros, M Snuderl, T Milde, RG Grundy, M Hoshino, SC Mack, RJ Gilbertson, DTW Jones, M Kool, A von Deimling, SM Pfister, F Sahm, D Kawauchi, KW Pajtler
- Journal:
- Cancer Discov
- Citation info:
- 11(9):2230-2247
- Publication date:
- 1st Sep 2021
- Full text
- DOI