Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to activation of the NF-kB signalling pathway

Supratentorial ependymomas differ from ependymomas of infratentorial or spinal location in respect to their clinical presentation, biology and genetics. We performed RNA sequencing and SNP6.0 profiling in 20 tumor samples. A novel recurrent fusion between C11orf95, a gene with unknown function, and RELA encoding the RelA p65 subunit of NF-kB was identified in 16/20 tumors. This fusion transcript resulted in an N-terminal part of C11orf95 part fused to RelA that is thereby uncoupled from its normal upstream regulators. Tumors carrying these fusions showed a strong upregulation of RELA mRNA. This fusion was not detected in a large series of infratentorial and spinal ependymomas, or other embryonal brain tumors. Immunohistochemistry showed that fusion positive cases had strong cytoplasmic and nuclear accumulation of RelA protein indicating an activation of NFkB signalling. Gene set enrichment analysis indicated that signatures characteristic for NFkB signalling itself and interferon signalling were significantly enriched in fusion-positive cases. In summary, C11orf95-RELA fusions represent a unique mechanism leading to activation of NFkB signalling in supratentorial ependymomas.