EPN-03C11orf95-RELA FUSION POSITIVE PEDIATRIC SUPRATENTORIAL EPENDYMOMAS ARE AN AGGRESSIVE SUBSET WITH INCREASED EXPRESSION OF STEM CELL MARKER NESTIN AND VASCULAR ENDOTHELIAL DERIVED GROWTH FACTOR

Abstract

C11orf95-RELA fusion was recently identified as a driver mutation in a subset of pediatric supratentorial ependymomas with poor outcome. We had previously demonstrated frequent expression of stem cell marker nestin and vascular endothelial derived growth factor (VEGF) in a group of Grade II/III supratentorial ependymomas showing frequent recurrences. We aimed to evaluate the incidence of RELA fusions in ependymomas and correlate it with clinicopathological features including immunoexpression of nestin and VEGF. Methods: 60 ependymoma cases (8 Grade I ependymomas, 23 Grade II ependymomas and 29 Grade III ependymomas) were analysed for RELAFUS1 (C11orf95 exon 2: RELA exon2) and RELAFUS2 (C11orf95 exon 3: RELA exon 2) using quantitative real time PCR and confirmed using Sanger sequencing. Gene expression analysis for NFKB1 and immunohistochemistry for MIB-1, nestin, and VEGF were performed. Results: RELA fusions were unique to the Grade II and III supratentorial ependymomas, detected in 71% (15/21) of all cases, including 50% of Grade II (4/8) and 85% (11/13) of Grade III tumors. All patients who harboured RELA fusions were < 21 years of age. Fusion positive cases showed significant upregulation of NFKB1 transcripts (p = 0.002), hypercellularity, endothelial proliferation, MIB-1 labelling index ≥10% and frequent immunopositivity for nestinand VEGF. RELA fusions significantly associatedwith poor progression free survival in supratentorial ependymomas (p = 0.031), while histological grade did not (p = 0.416). Conclusion: Detection of RELA fusions in supratentorial ependymomas has important prognostic implications, surpassing the impact of histological grade. Evaluation of downstream molecules of NF-KB pathway and VEGF as potential therapeutic targets is warranted.