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 Melnick; C David Allis; Craig B Thompson; Arul M Chinnaiyan; Alexander R Judkins; Sriram Venneti

doi:10.1126/scitranslmed.aah6904

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

Sci Transl Med. 2016 Nov 23;8(366):366ra161. doi: 10.1126/scitranslmed.aah6904.

Authors

Jill Bayliss¹, Piali Mukherjee², Chao Lu³, Siddhant U Jain⁴, Chan Chung¹, Daniel Martinez⁵, Benjamin Sabari³, Ashley S Margol⁶, Pooja Panwalkar¹, Abhijit Parolia^{1

7}, Melike Pekmezci⁸, Richard C McEachin⁹, Marcin Cieslik^{1

7}, Benita Tamrazi¹⁰, Benjamin A Garcia¹¹, Gaspare La Rocca¹², Mariarita Santi⁵, Peter W Lewis⁴, Cynthia Hawkins^{13

14}, Ari Melnick², C David Allis³, Craig B Thompson¹², Arul M Chinnaiyan^{1

7}, Alexander R Judkins¹⁵, Sriram Venneti¹⁶

Affiliations

¹ Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA.
² Epigenomics Core Facility, Weill Medical College of Cornell University, New York, NY 10065, USA.
³ Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, NY 10065, USA.
⁴ Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.
⁵ Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
⁷ Michigan Center for Translational Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48104, USA.
⁸ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48104, USA.
¹⁰ Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
¹¹ Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹² Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹³ Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁴ Faculty of Medicine, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
¹⁵ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. ajudkins@chla.usc.edu svenneti@med.umich.edu.
¹⁶ Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA. ajudkins@chla.usc.edu svenneti@med.umich.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain Neoplasms / diagnosis*
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Central Nervous System / pathology
Child
CpG Islands
DNA Methylation*
Ependymoma / diagnosis*
Ependymoma / genetics
Ependymoma / metabolism*
Epigenesis, Genetic
Gene Expression Profiling
Genome, Human
Histones / chemistry*
Humans
Mutation
Prognosis
Treatment Outcome

Substances

Histones

Abstract

Publication types

MeSH terms

Substances

Grants and funding