Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/89279
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Type: Journal article
Title: Identification of a neuronal transcription factor network involved in medulloblastoma development
Author: Lastowska, M.
Al-Afghani, H.
Al-Balool, H.
Sheth, H.
Mercer, E.
Coxhead, J.
Redfern, C.
Peters, H.
Burt, A.
Santibanez-Koref, M.
Bacon, C.
Chesler, L.
Rust, A.
Adams, D.
Williamson, D.
Clifford, S.
Jackson, M.
Citation: Acta neuropathologica communications, 2013; 1(1):35-1-35-16
Publisher: BioMed Central
Issue Date: 2013
ISSN: 2051-5960
2051-5960
Statement of
Responsibility: 
Maria Łastowska, Hani Al-Afghani, Haya H Al-Balool, Harsh Sheth, Emma Mercer, Jonathan M Coxhead, Chris PF Redfern, Heiko Peters, Alastair D Burt, Mauro Santibanez-Koref, Chris M Bacon, Louis Chesler, Alistair G Rust, David J Adams, Daniel Williamson, Steven C Clifford, and Michael S Jackson
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.
Keywords: Medulloblastoma; Mutagenesis; Transcription network; Differentiation
Rights: © 2013 Łastowska et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
RMID: 0030007611
DOI: 10.1186/2051-5960-1-35
Appears in Collections:Medicine publications

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