Publications (2)72.56 Total impact
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Article: Novel mutations target distinct subgroups of medulloblastoma
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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. Medulloblastoma is the most common malignant childhood brain tumour 1 . The disease includes four subgroups (sonic hedgehog (SHH) subgroup, WNT subgroup, subgroup 3 and subgroup 4), defined primarily by gene expression profiling, that show differences in karyotype, histology and prognosis 2 . Studies of genetically engineered mice show that these tumours arise from different cell types: SHH-subgroup medulloblastomas develop from committed cerebellar granule neuron progenitors (GNPs) in Ptch1 1/2 mice 3,4 ; WNT-subgroup tumours are generated by lower rhombic lip progenitors (LRLPs) in Blbp-Cre;Ctnnb1 1/lox(Ex3) ;Tp53 flx/flx mice 5 ; whereas subgroup-3 medulloblastomas probably arise from an undefined class of cerebellar progenitors 6 . The identification of medulloblastoma sub-groups has not changed clinical practice. All patients currently receive the same combination of surgery, radiation and chemotherapy. This aggressive treatment fails to cure two thirds of patients with subgroup-3 disease, and probably over-treats children with WNT-subgroup medulloblastoma who invariably survive with long-term cognitive and endocrine side effects 2,7 . Drugs targeting the genetic alterations that drive each medulloblastoma subgroup could prove more effective and less toxic, but the identity of these alterations remains largely unknown.Nature 06/2012; · 36.28 Impact Factor -
Article: Novel mutations target distinct subgroups of medulloblastoma.
[show abstract] [hide abstract]
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.Nature 06/2012; 488(7409):43-8. · 36.28 Impact Factor
Top co-authors
Institutions
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2012
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St. Jude Children's Research Hospital
Memphis, TN, USA
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