TitleLowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas.
Publication TypeJournal Article
Year of Publication2016
AuthorsBayliss, Jill, Mukherjee Piali, Lu Chao, Jain Siddhant U., Chung Chan, Martinez Daniel, Sabari Benjamin, Margol Ashley S., Panwalkar Pooja, Parolia Abhijit, Pekmezci Melike, McEachin Richard C., Cieslik Marcin, Tamrazi Benita, Garcia Benjamin A., La Rocca Gaspare, Santi Mariarita, Lewis Peter W., Hawkins Cynthia, Melnick Ari, C Allis David, Thompson Craig B., Chinnaiyan Arul M., Judkins Alexander R., and Venneti Sriram
JournalSci Transl Med
Volume8
Issue366
Pagination366ra161
Date Published2016 Nov 23
ISSN1946-6242
KeywordsBrain Neoplasms, Central Nervous System, Child, CpG Islands, DNA Methylation, Ependymoma, Epigenesis, Genetic, Gene Expression Profiling, Genome, Human, Histones, Humans, Mutation, Prognosis, Treatment Outcome
Abstract

<p>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.</p>

DOI10.1126/scitranslmed.aah6904
Alternate JournalSci Transl Med
PubMed ID27881822
PubMed Central IDPMC5123566
Grant ListK08 CA181475 / CA / NCI NIH HHS / United States
R01 CA177828 / CA / NCI NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 GM110174 / GM / NIGMS NIH HHS / United States