title: The genetic landscape of the childhood cancer medulloblastoma.
abstract: Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors.forename: D Williams
authors.initials: DW
authors.lastname: Parsons
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Zhang
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Leary
authors.forename: Jimmy Cheng-Ho
authors.initials: JC
authors.lastname: Lin
authors.forename: Simina M
authors.initials: SM
authors.lastname: Boca
authors.forename: Hannah
authors.initials: H
authors.lastname: Carter
authors.forename: Josue
authors.initials: J
authors.lastname: Samayoa
authors.forename: Chetan
authors.initials: C
authors.lastname: Bettegowda
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gallia
authors.forename: George I
authors.initials: GI
authors.lastname: Jallo
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Binder
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nikolsky
authors.forename: James
authors.initials: J
authors.lastname: Hartigan
authors.forename: Doug R
authors.initials: DR
authors.lastname: Smith
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Fults
authors.forename: Scott
authors.initials: S
authors.lastname: VandenBerg
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Suely Kazue Nagahashi
authors.initials: SK
authors.lastname: Marie
authors.forename: Sueli Mieko Oba
authors.initials: SM
authors.lastname: Shinjo
authors.forename: Carlos
authors.initials: C
authors.lastname: Clara
authors.forename: Peter C
authors.initials: PC
authors.lastname: Phillips
authors.forename: Jane E
authors.initials: JE
authors.lastname: Minturn
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Biegel
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Judkins
authors.forename: Adam C
authors.initials: AC
authors.lastname: Resnick
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Storm
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.forename: B Ahmed
authors.initials: BA
authors.lastname: Rasheed
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Roger
authors.initials: R
authors.lastname: McLendon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Peter C
authors.initials: PC
authors.lastname: Burger
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.forename: Nick
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
mesh_terms: D000328:Adult; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism; D002648:Child; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D052138:Genes, Neoplasm; D016147:Genes, Tumor Suppressor; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C452979:KMT2C protein, human; C120898:KMT2D protein, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D011495:Histone-Lysine N-Methyltransferase