Research ArticleCancer

Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas

Science Translational Medicine  23 Nov 2016:
Vol. 8, Issue 366, pp. 366ra161
DOI: 10.1126/scitranslmed.aah6904

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Epigenetics helps find the bad tumors

Ependymomas are brain tumors that can occur in people of all ages and in different parts of the central nervous system. The prognosis of these tumors does not necessarily correlate with clinical characteristics or even tumor grade, and there are no recurrent genetic mutations that can be used to classify these tumors. To address this problem, Bayliss et al. examined the epigenetics of ependymoma. By doing this, the authors identified some characteristic methylation patterns that correlate with prognosis, including one specific pattern that is also seen in childhood gliomas and associated with more invasive tumors.

Abstract

Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations, but a subset of these ependymomas exhibits CpG island (CpGi) hypermethylation [PF group A (PFA)], implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF-ve ependymomas) analogous to H3K27M mutant gliomas. PF-ve tumors exhibited many clinical and biological similarities with PFA ependymomas. Genomic H3K27me3 distribution showed an inverse relationship with CpGi methylation, suggesting that CpGi hypermethylation drives low H3K27me3 in PF-ve ependymomas. Despite CpGi hypermethylation and global H3K27me3 reduction, these tumors showed DNA hypomethylation in the rest of the genome and exhibited increased H3K27me3 genomic enrichment at limited genomic loci similar to H3K27M mutant gliomas. Combined integrative analysis of PF-ve ependymomas with H3K27M gliomas uncovered common epigenetic deregulation of select factors that control radial glial biology, and PF radial glia in early human development exhibited reduced H3K27me3. Finally, H3K27me3 immunostaining served as a biomarker of poor prognosis and delineated radiologically invasive tumors, suggesting that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.

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