Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
Acta Neuropathol Commun. 2013 Jul 11;1:35. doi: 10.1186/2051-5960-1-35.
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.
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.
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.
成神经管细胞瘤是最常见的儿童脑恶性肿瘤，至少包含 4 种不同的临床遗传学亚群。约 25%的肿瘤存在异常的 sonic hedgehog（SHH）信号，这定义了一个亚群。尽管这些肿瘤中存在 SHH 通路基因（如 PTCH1、SUFU）的改变，但高通量基因组分析仅发现了少数其他的反复突变。在此，我们利用 Sleeping Beauty 转座子系统对 Ptch+/-鼠肿瘤模型进行了诱变，以鉴定参与 SHH 亚群成神经管细胞瘤发生的其他基因和通路。
诱变显著增加了成神经管细胞瘤的发生频率，并鉴定出 17 个候选癌症基因，包括人类疾病中体细胞突变（PTEN、CREBBP）或与不良预后相关的基因（PTEN、MYT1L）的同源基因。引人注目的是，这些候选基因富含转录因子（p=2x10-5），其中大多数（6/7；Crebbp、Myt1L、Nfia、Nfib、Tead1 和 Tgif2）都位于一个单一的调控网络中，该网络富含与分化神经元表型相关的基因。此外，该网络在人类亚群之间的活性差异显著，与转移性疾病相关，并特异性地预测了 SHH 亚群肿瘤的不良生存。此前在成神经管细胞瘤中被牵连的 Igf2 是受网络干扰的鼠肿瘤中差异表达最显著的基因，并且在人和鼠肿瘤中，网络活性都表现为富集了多个基因集，表明细胞增殖增加、IGF 信号增强、MYC 靶基因上调和神经元分化减少。
总的来说，我们的数据支持在 SB 诱变的 Ptch+/-鼠中发生成神经管细胞瘤的模型，该模型涉及破坏一个新的转录因子网络，导致 Igf2 上调、GNPs 增殖和肿瘤形成。此外，我们的结果为 SHH 亚群肿瘤确定了合理的治疗靶点，并为识别 SHH 患者的不良风险提供了预后生物标志物。
