Lowered H3K27me3 and DNA Hypomethylation Define Poorly Prognostic Pediatric Posterior Fossa Ependymomas

Overview

Journal Sci Transl Med

Specialties General Medicine
Science

Date 2016 Nov 25

PMID 27881822

Citations 95

Authors

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 Melnick

C David Allis

Craig B Thompson

Arul M Chinnaiyan

Alexander R Judkins

Sriram Venneti

Affiliations

Soon will be listed here.

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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