Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling 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 a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95–RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
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Sequence and array data were deposited in the European Bioinformatics Institute (EBI) under accession number EGAS00001000254.
This research was supported as part of the St. Jude Children’s Research Hospital, Washington University Pediatric Cancer Genome Project. This work was supported by grants from the National Institutes of Health (R01CA129541, P01CA96832 and P30CA021765 to R.J.G), the Collaborative Ependymoma Research Network (CERN), and by the American Lebanese Syrian Associated Charities (ALSAC). We are grateful to S. Temple for the gift of reagents and the staff of the Hartwell Center for Bioinformatics and Biotechnology, Animal Imaging Center, and Flow Cytometry and Cell Sorting Shared Resource at St. Jude Children’s Research Hospital for technical assistance.
Extended data figures
This file contains Supplementary Tables 1-6 and comprises Table 1: Clinical, pathological and validated genetic abnormalities of all 177 tumors in the study cohort ; Table 2: Coverage data for tumours analyzed by whole genome sequencing; Table 3: Coverage data for tumors analyzed by RNASeq; able 4: Tier 1 validated and putative high quality SNV and indel mutations; Table 5: Tier 2 validated and putative high quality SNV and indel mutations; and Table S6: Tier 3 validated and putative high-quality SNVs and indel mutations.
This file contains Supplementary Tables 7-12 and comprises Table 7: Numbers of high quality validated and putative Tier1 SNVs and indel mutations detected by WGS; Table 8: Copy number variations in tumors from the discovery series analyzed by WGS; Table 9: Copy number alterations detected by SNP 6 arrays; Table 10: Summary of All Genetic Aberrations Found by WGS; Table 11: Counts of structural variations detected by CREST in samples analyzed by WGS; and Table 12: Statistical analysis of chromothripsis status within 11q13.1.
This file contains Supplementary Tables 13-18 and comprises Table 13: Validated and uncovered fusion builder predictions from WGS; Table 14: Primers used for SV validation; Table 15: iFISH probes; Table 16a: C11orf95-RELA fusions predicted by RNA-seq; Table 16b: Fusions involving C11orf95 but not RELA; Table 16c: Additional fusions not involving C11orf95; Table 17a: Significantly activated transcription regulators identified by Ingenuity Pathway Analysis; Table 17b: Significant networks identified by analysis of differential gene expression data or RNASeq data & highlighting NF-kB; Table 18a: Pathway analysis of genes upregulated by RELAWT in NSCs and Table 18b: Pathway analysis of genes upregulated by RELAFUS1 in NSCs