Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD
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CREB-Binding Protein / genetics
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Cadherins / genetics
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Cdh1 Proteins
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Cell Cycle Proteins / deficiency
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Cell Cycle Proteins / genetics
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Cell Lineage
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Cerebellar Neoplasms / classification*
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Cerebellar Neoplasms / genetics*
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Cerebellar Neoplasms / pathology
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Child
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Class I Phosphatidylinositol 3-Kinases
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DEAD-box RNA Helicases / genetics
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DNA Copy Number Variations
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DNA Helicases / genetics
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DNA Mutational Analysis
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Disease Models, Animal
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Genome, Human / genetics
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Genomics
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Hedgehog Proteins / metabolism
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Histone Demethylases / genetics
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Histones / metabolism
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Humans
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Medulloblastoma / classification*
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Medulloblastoma / genetics*
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Medulloblastoma / pathology
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Methylation
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Mice
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Mutation / genetics*
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Nuclear Proteins / genetics
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Phosphatidylinositol 3-Kinases / genetics
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Transcription Factors / genetics
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Wnt Proteins / metabolism
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beta Catenin / genetics
Substances
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Antigens, CD
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CDH1 protein, human
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CTNNB1 protein, human
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Cadherins
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Cdh1 Proteins
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Cell Cycle Proteins
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Fzr1 protein, mouse
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Hedgehog Proteins
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Histones
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Nuclear Proteins
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SHH protein, human
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Transcription Factors
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Wnt Proteins
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ZMYM3 protein, human
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beta Catenin
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Histone Demethylases
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KDM6A protein, human
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CREB-Binding Protein
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CREBBP protein, human
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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DDX3X protein, human
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SMARCA4 protein, human
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DNA Helicases
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DEAD-box RNA Helicases