Identification of a neuronal transcription factor network involved in medulloblastoma development

Abstract

BackgroundMedulloblastomas, 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.ResultsMutagenesis 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.ConclusionsCollectively, 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.

Identification of FoxR2 as an Oncogene in Medulloblastoma

“…Interestingly, nearly 40% of genes identified in our screen were associated with transcription, consistent with a previous screen for medulloblastoma disease genes (49). Transcription factors play essential roles in coordinated gene expression during development.…”

Nuclear factor one transcription factors: Divergent functions in developmental versus adult stem cell populations

“…For example, if NFIs drive differentiation during development, then it is a strong possibility that inactivating mutations in Nfi genes will be identified in developmental based cancers. Indeed, as discussed in this review, there are a number of recent studies that have shown a potential role for inactivating mutations in NFIs in contributing to medulloblastoma, the most common childhood brain cancer (Wu et al, 2012; Genovesi et al, 2013; Lastowska et al, 2013). It might therefore be interesting to determine whether NFIs act as oncogenes in adult-derived cancers, particularly as these cancers are thought to be caused by deregulated or chronic repair mechanisms, whereby stem cells are recruited to repopulate tissues.…”

“…Medulloblastoma is a common malignant brain tumour of childhood, and certain subtypes of this disease have long been known to arise from GNPs of the EGL (Marino et al, 2000; Oliver et al, 2005; Schuller et al, 2008). Recently, a number of studies have identified NFI factors as being involved in medulloblastoma tumorigenesis, with transposon-mediated inactivation of Nfia, Nfib and/or Nfix shown to accelerate medulloblastoma initiation and/or progression in mouse models of medulloblastoma derived from GNPs (Wu et al, 2012; Genovesi et al, 2013; Lastowska et al, 2013). Indeed, a role for Nfia in medulloblastoma formation in vivo was recently supported by data showing that combined haploinsufficiency for both Nfia and Ptch1 exacerbated tumour development compared to the Ptch1 haploinsufficiency alone (Genovesi et al, 2013).…”

The function of NFIX during developmental and adult neurogenesis

“…Indeed, as discussed in this review, there are a number of recent studies that have shown a potential role for inactivating mutations in NFIs in driving tumorigenesis in medulloblastoma, the most common childhood brain cancer (Wu et al, 2012;Genovesi et al, 2013;Lastowska et al, 2013). It might therefore be interesting to determine whether NFIs act as oncogenes in adult-derived cancers, particularly as these cancers are thought to be caused by deregulated or chronic repair mechanisms, whereby stem cells are recruited to repopulate tissues.…”

“…Medulloblastoma is a common malignant brain tumour of childhood, and certain subtypes of this disease have long been known to arise from GNPs of the EGL (Marino et al, 2000;Oliver et al, 2005;Schuller et al, 2008). Recently, a number of studies identified NFI factors as potential drivers of medulloblastoma tumorigenesis, with transposonmediated inactivation of Nfia, Nfib and/or Nfix shown to accelerate medulloblastoma initiation and/or progression in a mouse model of medulloblastoma derived from GNPs (Wu et al, 2012;Genovesi et al, 2013;Lastowska et al, 2013). Nfia was subsequently confirmed as a specific driver of medulloblastoma in vivo, with combined haploinsufficiency for both Nfia and Ptch1 exacerbating tumour development compared to the Ptch1 haploinsufficiency alone (Genovesi et al, 2013).…”