Department of Neurosurgery, Necker-Sick Children Hospital, University Paris V Descartes, Paris, France.
PLoS One. 2012;7(2):e30313. doi: 10.1371/journal.pone.0030313. Epub 2012 Feb 28.
Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies.
弥漫性内在脑桥神经胶质瘤（DIPG）是最常见的儿童脑恶性肿瘤之一，其预后普遍致命。在过去的三十年中，标准的放疗治疗方法并没有显著改善。为了解决对 DIPG 认识不足的问题，我们对通过立体定向活检获得的大量样本进行了综合分子分析。虽然染色体不平衡在 CGHarrays 上不能区分 DIPG 和幕上肿瘤，但基因表达谱分析显示它们之间存在明显差异，脑干神经胶质瘤类似于中线/丘脑肿瘤，表明起源密切相关。确定了两种不同的 DIPG 亚组。第一个亚组表现出间充质和促血管生成特征，具有干细胞标志物富集，这表明可以从这些活检中生长肿瘤干细胞。另一个亚组表现出少突胶质细胞特征，并且主要受到 PDGFRA 的驱动，特别是通过在细胞外结构域中扩增和/或新的错义突变。在后一组患者中，早期死亡的风险比（即在 10 个月之前）高 8 倍，与另一亚组相比，其风险显著更高（p = 0.041，Cox 回归模型）。在一系列 55 例石蜡包埋活检样本中，证实了具有少突胶质细胞类型肿瘤的患者预后更差（中位 OS 为 7.73 与 12.37 个月，p = 0.045，对数秩检验）。在诊断时，可以通过少突胶质细胞分化或间充质转化，分别定义具有特定基因组改变的 DIPG 的两个不同转录亚组。通过信号转导通路激活和通路成员基因的突变对这些肿瘤进行分类，对于开发靶向治疗可能特别有价值。
