Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion–Positive Supratentorial Ependymomas

Abstract

Molecular groups of supratentorial ependymomas comprise tumors with <i>ZFTA-RELA</i> or <i>YAP1</i>-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 <i>ZFTA</i> as a partner gene. Somatic overexpression of <i>ZFTA</i>-associated fusion genes in the developing cerebral cortex is capable of inducing tumor formation <i>in vivo</i>, and cross-species comparative analyses identified <i>GLI2</i> 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: <i>ZFTA-RELA</i> 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 <i>ZFTA</i> fusion-positive tumors, such as GLI2.<i>This article is highlighted in the In This Issue feature, p. 2113</i>.