Cooperating Pathways in Gliomagenesis

描述（由申请人提供）：成人或儿童胶质母细胞瘤在很大程度上仍然无法治愈。虽然两个年龄组中的胶质瘤靶向共同的通路，但每个通路中特定突变的频率在年龄组之间不同。尽管儿童和成人胶质母细胞瘤具有相似的组织病理学特征，但大约一半的儿童胶质母细胞瘤在脑干中以弥漫性内在脑桥胶质瘤（DIPG）的形式出现，这是一种几乎仅发生在儿童中的疾病。我们小组和其他人最近的研究表明，不同年龄组的胶质瘤致癌驱动因素存在显着差异。最值得注意的是，频繁的组蛋白H3突变是儿科疾病特有的，与非脑干儿科胶质母细胞瘤相比，DIPG中的频率和特异性突变存在显著差异。因此，胶质母细胞瘤的出现是多个途径中协同突变的结果，一些在成人和儿科疾病之间共享，而另一些则是特定发育环境所特有的。在我们未发表的112例儿童高级别胶质瘤（包括54例DIPG）的基因组测序分析中，我们在32%的DIPG中发现了BMP受体ACVR 1的体细胞激活错义突变，但在非脑干高级别胶质瘤中没有发现，这在脑干发育的背景下显示了独特的选择性优势。我们还确定了涉及三个神经营养因子受体（NTRK）基因和五个不同的N-末端融合伴侣的激酶结构域的基因融合。这些融合在来自三岁以下儿童的40%的非脑干高级别胶质瘤中发现，并且在来自较大儿童的DIPG和非脑干高级别胶质瘤中的频率较低。其他人最近的研究也发现了儿童低级别胶质瘤和成人胶质母细胞瘤中的NTRK融合。因此，这些改变在多种发育环境中的胶质瘤发生中发挥作用。本申请研究了特定突变如何提供选择性优势并在选择的发育环境中促进肿瘤发生，还探索了PI 3 K信号传导的贡献，该信号传导在所有年龄组的胶质瘤中被破坏。充分了解这些突变的转化机制和下游效应对于这些致命疾病的选择性治疗方法的知情设计至关重要。

DESCRIPTION (provided by applicant): Glioblastomas arising in adults or children remain largely incurable. While gliomas in both age groups target common pathways, the frequency of specific mutations in each pathway differ between age groups. Although pediatric and adult glioblastoma have similar histopathological features, approximately half of all pediatric glioblastomas arise in the brainstem as diffuse intrinsic pontine gliomas (DIPGs), a disease that occurs almost exclusively in children. Recent studies from our group and others showed significant differences in the oncogenic drivers of glioma in different age groups. Most notably, frequent histone H3 mutations are specific to pediatric disease, with striking differences in the frequency and specific mutation in DIPG compared to non- brainstem pediatric glioblastomas. Thus, glioblastomas arise as the result of cooperating mutations in multiple pathways, some shared between adult and pediatric disease, and others unique to specific developmental contexts. In our unpublished genomic sequencing analysis of 112 pediatric high-grade gliomas, including 54 DIPGs, we identified somatic activating missense mutations in the BMP receptor ACVR1 in 32% of DIPGs, but not in non-brainstem high-grade gliomas, showing a unique selective advantage in the context of developing brainstem. We also identified gene fusions involving the kinase domain of each of the three neurotrophin receptor (NTRK) genes and five different N-terminal fusion partners. These fusions were found in 40% of non- brainstem high-grade gliomas from children under three years old, and at lower frequency in both DIPG and non-brainstem high-grade gliomas from older children. Recent studies from others also identified NTRK fusions in pediatric low-grade gliomas and adult glioblastomas. Thus, these alterations play a role in gliomagenesis in multiple developmental settings. This application investigates how specific mutations provide a selective advantage and contribute to tumorigenesis in select developmental settings, also exploring the contribution of PI3K signaling, which is disrupted in gliomas of all age groups. A full understanding of the mechanisms of transformation and downstream effects of these mutations are critical to the informed design of selective therapeutics for these deadly diseases.