title: Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas.
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.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Bayliss
authors.affiliation: Epigenomics Core Facility, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Piali
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, NY 10065, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.
authors.forename: Siddhant U
authors.initials: SU
authors.lastname: Jain
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: Chan
authors.initials: C
authors.lastname: Chung
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martinez
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, NY 10065, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sabari
authors.affiliation: Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Margol
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Panwalkar
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA.|Michigan Center for Translational Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Parolia
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Melike
authors.initials: M
authors.lastname: Pekmezci
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: McEachin
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA.|Michigan Center for Translational Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Cieslik
authors.affiliation: Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
authors.forename: Benita
authors.initials: B
authors.lastname: Tamrazi
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Gaspare
authors.initials: G
authors.lastname: La Rocca
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Santi
authors.affiliation: Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Faculty of Medicine, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: Epigenomics Core Facility, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, NY 10065, USA.
authors.forename: C
authors.initials: C
authors.lastname: David Allis
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA.|Michigan Center for Translational Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48104, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: 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.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Judkins
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA. ajudkins@chla.usc.edu svenneti@med.umich.edu.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
mesh_terms: D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000473:pathology; D002648:Child; D018899:CpG Islands; D019175:DNA Methylation; D004806:Ependymoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015894:Genome, Human; D006657:Histones / Q000737:chemistry*; D006801:Humans; D009154:Mutation; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D006657:Histones