C11orf95–RELA fusions drive oncogenic NF-κB signalling in ependymoma

Abstract

The nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells-the cell of origin of ependymoma-to form these tumours in mice. Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.

The landscape of genomic alterations across childhood cancers

“…External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).…”

“…Ninety-five per cent of the patients were under 18 years of age (or age unspecified but confirmed age group paediatric), but available data were included for patients up to 25 years, as these were considered relevant for cancer types that typically peak at a young age. All centres have approved data access and informed consent had been obtained from all patients.External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).The final cohort included 914 individual patients of no more than 25 years of age including primary tumours for 879 patients with 47 matched relapsed tumours, and an additional 35 independent relapsed tumours ( Supplementary Tables 1, 2). Deep-sequencing (~ 30× ) whole-genome data (WGS) were available for 547 samples with matched control, whole-exome sequencing (WES) for 414, and low-coverage whole-genome sequencing (lcWGS) for an additional 54 germline and 186 tumour samples.…”

Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling

“…We report here a series of 20 clear cell ependymomas with branching capillaries and show that these tumors have a characteristic clinico-radiological presentation, pathological features, and pathological activation of the NFkB signaling pathway, with nuclear p65RelA accumulation in almost all cases as a result of C11ORF95-RELA fusions as described by Pietsch et al 10 and Parker et al 11 Although the frequency of clear cell ependymomas is unknown in the literature, it seems very rare according to the few series reported. 12,13 The 20 cases included in our work were collected over a period of 20 years.…”

“…10,11 Although 7 distinct C11ORF95-RELA fusion transcripts have been reported, 11 the most frequent included exons 1 -2 of C11ORF95 and, except for the first codons, the entire open reading frame of RELA (this fusion was called RELA FUS1 by the authors).…”

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

“…Greater than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NFκB subunit RELA (ST-EPN-RELA), and less frequently involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). 1,3,4 Subependymomas, a distinct histologic variant, can also be found within the ST and PF compartments accounting for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE, respectively 1 . Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts with the goal of identifying essential super enhancer associated genes on which tumour cells were dependent.…”