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

authors

• Zheng Tuyu
• Ghasemi David
• Okonechnikov Konstantin
• Korshunov Andrey
• Sill Martin
• Maass Kendra
• Benites Goncalves da Silva Patricia
• Ryzhova Marina
• Gojo Johannes
• Stichel Damian
• Arabzade Amir
• Kupp Robert
• Benzel Julia
• Taya Shinichiro
• Adachi Toma
• Shiraishi Ryo
• Gerber Nicolas
• Sturm Dominik
• Ecker Jonas
• Sievers Philipp
• Selt Florian
• Chapman Rebecca
• Haberler Christine
• Figarella‑branger Dominique
• Reifenberger Guido
• Fleischhack Gudrun
• Rutkowski Stefan
• Donson Andrew
• Ramaswamy Vijay
• Capper David
• Ellison David
• Herold-Mende Christel
• Schuller Ulrich
• Brandner Sebastian
• Hernaiz Driever Pablo
• Kros Johan
• Snuderl Matija
• Milde Till
• Grundy Richard
• Hoshino Mikio
• Mack Stephen
• Gilbertson Richard
• Jones David T.W.
• Kool Marcel
• von Deimling Andreas
• Pfister Stefan
• Sahm Felix
• Kawauchi Daisuke
• Pajtler Kristian

keywords

• Ependymoma
• Supratentorial
• PLAGL1
• EWSR1
• FOXO1
• EP300
• Gene fusion

document type

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 histological 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.

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