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Novel mutations target distinct subgroups of medulloblastoma.

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

Pubmed ID: 22722829


  • Robinson G
  • Parker M
  • Kranenburg TA
  • Lu C
  • Chen X
  • Ding L
  • Phoenix TN
  • Hedlund E
  • Wei L
  • Zhu X
  • Chalhoub N
  • Baker SJ
  • Huether R
  • Kriwacki R
  • Curley N
  • Thiruvenkatam R
  • Wang J
  • Wu G
  • Rusch M
  • Hong X
  • Becksfort J
  • Gupta P
  • Ma J
  • Easton J
  • Vadodaria B
  • Onar-Thomas A
  • Lin T
  • Li S
  • Pounds S
  • Paugh S
  • Zhao D
  • Kawauchi D
  • Roussel MF
  • Finkelstein D
  • Ellison DW
  • Lau CC
  • Bouffet E
  • Hassall T
  • Gururangan S
  • Cohn R
  • Fulton RS
  • Fulton LL
  • Dooling DJ
  • Ochoa K
  • Gajjar A
  • Mardis ER
  • Wilson RK
  • Downing JR
  • Zhang J
  • Gilbertson RJ



Publication Data

August 2, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: P01 CA096832
  • Agency: NCI NIH HHS, Id: P01CA96832
  • Agency: NCI NIH HHS, Id: P30 CA021765
  • Agency: NCI NIH HHS, Id: P30CA021765
  • Agency: NCI NIH HHS, Id: R01 CA129541
  • Agency: NCI NIH HHS, Id: R01CA129541

Mesh Terms

  • Animals
  • CREB-Binding Protein
  • Cadherins
  • Cdh1 Proteins
  • Cell Cycle Proteins
  • Cell Lineage
  • Cerebellar Neoplasms
  • Child
  • DEAD-box RNA Helicases
  • DNA Copy Number Variations
  • DNA Helicases
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Genome, Human
  • Genomics
  • Hedgehog Proteins
  • Histone Demethylases
  • Histones
  • Humans
  • Medulloblastoma
  • Methylation
  • Mice
  • Mutation
  • Nuclear Proteins
  • Phosphatidylinositol 3-Kinases
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin