title: Identification of a neuronal transcription factor network involved in medulloblastoma development.
abstract: 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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. michael.jackson@newcastle.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Lastowska
authors.forename: Hani
authors.initials: H
authors.lastname: Al-Afghani
authors.forename: Haya H
authors.initials: HH
authors.lastname: Al-Balool
authors.forename: Harsh
authors.initials: H
authors.lastname: Sheth
authors.forename: Emma
authors.initials: E
authors.lastname: Mercer
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Coxhead
authors.forename: Chris P F
authors.initials: CP
authors.lastname: Redfern
authors.forename: Heiko
authors.initials: H
authors.lastname: Peters
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Burt
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.forename: Chris M
authors.initials: CM
authors.lastname: Bacon
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Daniel
authors.initials: D
authors.lastname: Williamson
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.forename: Michael S
authors.initials: MS
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008297:Male; D008527:Medulloblastoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C513121:IGF2 protein, mouse; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D007335:Insulin-Like Growth Factor II