Abstract
C11ORF95–RELA fusions are common in one ependymoma subtype, but another has no recurrent mutations.
Major finding: C11ORF95–RELA fusions are common in one ependymoma subtype, but another has no recurrent mutations.
Concept: C11ORF95–RELA activates NF-κB signaling, and epigenetic alterations may drive genetically silent tumors.
Impact: These findings may explain ependymoma chemoresistance and suggest potential therapeutic strategies.
Ependymomas are malignant tumors of the central nervous system that are largely unresponsive to chemotherapy and often incurable by surgical resection and radiation therapy. Despite having similar histologic features, ependymomas from different anatomic sites are molecularly and clinically distinct. Parker and colleagues found that 67% of supratentorial ependymomas harbored a fusion between C11ORF95, a poorly characterized open reading frame, and RELA, which encodes a canonical NF-κB signaling pathway effector. Compared with wild-type RELA, the RELA fusion protein preferentially accumulated in the nucleus and led to increased NF-κB target gene activation. Furthermore, C11ORF95–RELA expression in neural stem cells implanted into mouse cerebrums led to the rapid development of aggressive tumors that recapitulated the features of supratentorial ependymoma. Interestingly, C11ORF95–RELA fusions were specific to supratentorial ependymomas, as no recurrent translocations were identified in posterior fossa ependymomas, which had an extremely low somatic mutation rate. In another study, Mack and colleagues also found that the somatic mutation rate was low in these tumors, and did not identify any significant recurrent mutations. Unlike posterior fossa type B (PFB) tumors, which frequently harbored recurrent large-scale copy number aberrations, posterior fossa type A (PFA) tumors were genomically stable. Instead, these tumors had increased CpG island methylation relative to PFB tumors that was consistent with a CpG island methylator phenotype. Many CpG-methylated genes in PFA ependymomas were Polycomb repressive complex 2 (PRC2) targets, and chromatin immunoprecipitation sequencing revealed significant overlap between histone H3 lysine 27 trimethylation (H3K27me3) and CpG methylation. Moreover, PFA ependymoma cells, but not supratentorial ependymoma cells, were highly sensitive to treatment with a DNA demethylating agent or with PRC2 inhibitors, suggesting that PFA ependymomas may be driven by epigenetic deregulation and that epigenetically based therapies may be effective in this ependymoma subtype. Together, these findings establish that ependymoma subtypes can arise through fundamentally distinct mechanisms and suggest rational strategies for ependymoma therapy.
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