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Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2013

Open Access 01-12-2013 | Research

Identification of a neuronal transcription factor network involved in medulloblastoma development

Authors: 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, Michael S Jackson

Published in: Acta Neuropathologica Communications | Issue 1/2013

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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.
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Metadata
Title
Identification of a neuronal transcription factor network involved in medulloblastoma development
Authors
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
Michael S Jackson
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2013
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/2051-5960-1-35

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