title: Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma.
abstract: Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Shing H
authors.initials: SH
authors.lastname: Zhan
authors.forename: Maria
authors.initials: M
authors.lastname: Mendez-Lago
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Alexander
authors.initials: A
authors.lastname: Unterberger
authors.forename: A Sorana
authors.initials: AS
authors.lastname: Morrissy
authors.forename: David
authors.initials: D
authors.lastname: Shih
authors.forename: John
authors.initials: J
authors.lastname: Peacock
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.forename: Adi
authors.initials: A
authors.lastname: Rolider
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
authors.forename: Sidney
authors.initials: S
authors.lastname: Croul
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D001483:Base Sequence; D002528:Cerebellar Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome; D056466:Histone Demethylases / Q000235:genetics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000145:classification / Q000235:genetics*; D006801:Humans; D008239:Lysine / Q000235:genetics*; D008297:Male; D008527:Medulloblastoma / Q000145:classification / Q000175:diagnosis / Q000235:genetics; D008745:Methylation; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine