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Lookup NU author(s): Dr Maria Lastowska, Hani Al-Afghani, Haya AL-Balool, Harsh SHETH, Dr Jonathan Coxhead, Dr Chris RedfernORCiD, Dr Heiko Peters, Professor Alastair BurtORCiD, Dr Mauro Santibanez Koref, Dr Christopher Bacon, Professor Steven CliffordORCiD, Dr Michael Jackson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Łastowska M, Al-Afghani H, Al-Balool HH, Sheth H, Mercer E, Coxhead JM, Redfern CPF, Peters H, Burt AD, Santibanez-Koref M, Bacon CM, Chesler L, Rust AG, Adams DJ, Williamson D, Clifford SC, Jackson MS
Publication type: Article
Publication status: Published
Journal: Acta Neuropathologica Communications
Year: 2013
Volume: 1
Online publication date: 11/07/2013
Date deposited: 17/10/2013
ISSN (electronic): 2051-5960
Publisher: BioMed Central Ltd
URL: http://dx.doi.org/10.1186/2051-5960-1-35
DOI: 10.1186/2051-5960-1-35
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