<italic>C11orf95-RELA</italic> fusions and upregulated NF-KB signalling characterise a subset of aggressive supratentorial ependymomas that express L1CAM and nestin.

Ependymomas (EPN) show site specific genetic alterations and a recent DNA methylation profiling study identified nine molecular subgroups. <italic>C11orf95-RELA</italic> and <italic>YAP1</italic> fusions characterise the RELA and YAP1 molecular subgroups, respectively, of supratentorial (ST)-EPNs. Current guidelines recommend molecular subgrouping over histological grade for accurate prognostication. Clinicopathological features of ST-EPNs in correlation with <italic>C11orf95-RELA</italic> and <italic>YAP1</italic> fusions have been assessed in only few studies. We aimed to study these fusions in EPNs, and identify diagnostic and prognostic markers. qRT-PCR and Sanger Sequencing for the detection of <italic>C11orf95-RELA, YAP1-MAMLD1</italic> and <italic>YAP1-FAM118B</italic> fusion transcripts, gene expression analysis for <italic>NFKB1</italic>, and immunohistochemistry for p53, MIB-1, nestin, VEGF, and L1CAM were performed. 88 EPNs (10-Grade I and 78-Grade II/III) from all sites were included. <italic>RELA</italic> fusions were unique to Grade II/III ST-EPNs, detected in 81.4% (22/27) and 18.5% (5/27) of pediatric and adult ST-EPNs respectively. ST-EPNs harbouring <italic>RELA</italic> fusions showed frequent grade III histology (81.5%), clear cell morphology (70.3%), upregulated <italic>NFKB1</italic> expression, MIB-1 labelling indices (LI) ≥ 10% (77.8%), and immunopositivity for nestin (95.7%), VEGF (72%), L1CAM (79%), and p53 (64%). Presence of <italic>RELA</italic> fusions, L1CAM immunopositivity and MIB-1 LI ≥ 10% associated with poor outcome. L1CAM showed 81% concordance with <italic>RELA</italic> fusions. <italic>YAP1-MAMLD1</italic> fusion was identified in a single RELA fusion negative adult anaplastic ST-EPN. <italic>RELA</italic> fusions are frequent in ST-EPNs and associate with poor outcome. L1CAM is a surrogate immunohistochemical marker. <italic>RELA</italic> fusion positive ST-EPNs strongly express nestin indicating increased stemness. Further evaluation of the interactions between NFKB and stem cell pathways is warranted. [ABSTRACT FROM AUTHOR]