title: Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.
abstract: We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.
authors.affiliation: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nakahara
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Wu
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Sid
authors.initials: S
authors.lastname: Croul
authors.forename: Stephen
authors.initials: S
authors.lastname: Mack
authors.forename: Paul N
authors.initials: PN
authors.lastname: Kongkham
authors.forename: John
authors.initials: J
authors.lastname: Peacock
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.forename: Young-Shin
authors.initials: YS
authors.lastname: Ra
authors.forename: Karen
authors.initials: K
authors.lastname: Zilberberg
authors.forename: Jessica
authors.initials: J
authors.lastname: McLeod
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: J
authors.initials: J
authors.lastname: Sunil Rao
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Wiesia
authors.initials: W
authors.lastname: Grajkowska
authors.forename: Yancey
authors.initials: Y
authors.lastname: Gillespie
authors.forename: Boleslaw
authors.initials: B
authors.lastname: Lach
authors.forename: Richard
authors.initials: R
authors.lastname: Grundy
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Timothy
authors.initials: T
authors.lastname: Van Meter
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Carlotti
authors.forename: Frederick
authors.initials: F
authors.lastname: Boop
authors.forename: Darrell
authors.initials: D
authors.lastname: Bigner
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D002528:Cerebellar Neoplasms / Q000201:enzymology / Q000235:genetics*; D005784:Gene Amplification; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D015894:Genome, Human; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008527:Medulloblastoma / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine