In:
Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 1, No. 1 ( 2013-12)
Abstract:
Medulloblastomas, the most frequent malignant brain tumours affecting
children, comprise at least 4 distinct clinicogenetic subgroups. Aberrant sonic hedgehog (SHH) signalling is observed in approximately 25% of tumours
and defines one subgroup. Although alterations in SHH pathway genes (e.g. PTCH1 , SUFU ) are observed in many of these tumours,
high throughput genomic analyses have identified few other recurring mutations. Here, we have mutagenised the Ptch +/- murine tumour model using the Sleeping Beauty transposon
system to identify additional genes and pathways involved in SHH subgroup medulloblastoma development. Results Mutagenesis significantly increased medulloblastoma frequency and identified 17 candidate cancer genes, including orthologs of genes somatically mutated
( PTEN, CREBBP ) or associated with poor outcome ( PTEN,
MYT1L ) in the human disease. Strikingly, these candidate genes were
enriched for transcription factors (p = 2x10 -5 ), the
majority of which (6/7; Crebbp , Myt1L , Nfia, Nfib,
Tead1 and Tgif2 ) were linked within a single regulatory
network enriched for genes associated with a differentiated neuronal phenotype. Furthermore, activity of this network varied significantly
between the human subgroups, was associated with metastatic disease, and predicted poor survival specifically within the SHH subgroup of tumours. Igf2 , previously implicated in medulloblastoma, was the most
differentially expressed gene in murine tumours with network perturbation, and network activity in both mouse and human tumours was characterised by
enrichment for multiple gene-sets indicating increased cell proliferation, IGF signalling, MYC target upregulation, and decreased neuronal
differentiation. Conclusions Collectively, our data support a model of medulloblastoma development in
SB-mutagenised Ptch +/- mice which involves disruption of a novel transcription
factor network leading to Igf2 upregulation, proliferation of GNPs,
and tumour formation. Moreover, our results identify rational therapeutic targets for SHH subgroup tumours, alongside prognostic biomarkers for the
identification of poor-risk SHH patients.
Type of Medium:
Online Resource
ISSN:
2051-5960
DOI:
10.1186/2051-5960-1-35
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2013
detail.hit.zdb_id:
2715589-4
