BACKGROUND: 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.