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

Jill Bayliss, Piali Mukherjee, Chao Lu, Siddhant U. Jain, Chan Chung, Daniel Martinez, Benjamin Sabari, Ashley S. Margol, Pooja Panwalkar, Abhijit Parolia, Melike Pekmezci, Richard C. McEachin, Marcin Cieslik, Benita Tamrazi, Benjamin A. Garcia, Gaspare La Rocca, Mariarita Santi, Peter W. Lewis, Cynthia Hawkins, Ari MelnickC. David Allis, Craig B. Thompson, Arul M. Chinnaiyan, Alexander R. Judkins, Sriram Venneti

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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. 2016

Original languageEnglish (US)
Article number6904
JournalScience translational medicine
Volume8
Issue number366
DOIs
StatePublished - Nov 23 2016
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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