title: Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.
abstract: Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors: Trevor J
authors: TJ
authors: Pugh
authors: Shyamal Dilhan
authors: SD
authors: Weeraratne
authors: Tenley C
authors: TC
authors: Archer
authors: Daniel A
authors: DA
authors: Pomeranz Krummel
authors: Daniel
authors: D
authors: Auclair
authors: James
authors: J
authors: Bochicchio
authors: Mauricio O
authors: MO
authors: Carneiro
authors: Scott L
authors: SL
authors: Carter
authors: Kristian
authors: K
authors: Cibulskis
authors: Rachel L
authors: RL
authors: Erlich
authors: Heidi
authors: H
authors: Greulich
authors: Michael S
authors: MS
authors: Lawrence
authors: Niall J
authors: NJ
authors: Lennon
authors: Aaron
authors: A
authors: McKenna
authors: James
authors: J
authors: Meldrim
authors: Alex H
authors: AH
authors: Ramos
authors: Michael G
authors: MG
authors: Ross
authors: Carsten
authors: C
authors: Russ
authors: Erica
authors: E
authors: Shefler
authors: Andrey
authors: A
authors: Sivachenko
authors: Brian
authors: B
authors: Sogoloff
authors: Petar
authors: P
authors: Stojanov
authors: Pablo
authors: P
authors: Tamayo
authors: Jill P
authors: JP
authors: Mesirov
authors: Vladimir
authors: V
authors: Amani
authors: Natalia
authors: N
authors: Teider
authors: Soma
authors: S
authors: Sengupta
authors: Jessica Pierre
authors: JP
authors: Francois
authors: Paul A
authors: PA
authors: Northcott
authors: Michael D
authors: MD
authors: Taylor
authors: Furong
authors: F
authors: Yu
authors: Gerald R
authors: GR
authors: Crabtree
authors: Amanda G
authors: AG
authors: Kautzman
authors: Stacey B
authors: SB
authors: Gabriel
authors: Gad
authors: G
authors: Getz
authors: Natalie
authors: N
authors: Jäger
authors: David T W
authors: DT
authors: Jones
authors: Peter
authors: P
authors: Lichter
authors: Stefan M
authors: SM
authors: Pfister
authors: Thomas M
authors: TM
authors: Roberts
authors: Matthew
authors: M
authors: Meyerson
authors: Scott L
authors: SL
authors: Pomeroy
authors: Yoon-Jae
authors: YJ
authors: Cho
mesh_terms: D002528:Cerebellar Neoplasms / Q000145:classification / Q000235:genetics*; D002648:Child; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D053823:Hedgehog Proteins / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D060588:LIM Domain Proteins / Q000235:genetics; D008527:Medulloblastoma / Q000145:classification / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C411984:BCOR protein, human; C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; C103316:GPS2 protein, human; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; C120898:KMT2D protein, human; C486312:LDB1 protein, human; D060588:LIM Domain Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C509239:SHH protein, human; D051820:TCF Transcription Factors; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D051176:beta Catenin; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C119332:DDX3X protein, human; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D053487:DEAD-box RNA Helicases