Cooperating Pathways in Gliomagenesis

神经胶质瘤发生中的合作途径

• 批准号: 8766268
• 负责人: SUZANNE J BAKER
• 金额: $ 36.94万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-02 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766268
• 关键词: 3 year old; ACVR1 gene; Adult; Adult Glioblastoma; Autopsy; Biological; Brain; Brain Stem; Brain region; Cells; Child; Childhood; Childhood Brain Neoplasm; Childhood Glioblastoma; Code; Complex; Development; Diagnosis; Diffuse; Disease; ETV6 gene; Employee Strikes; Family; Frequencies; Gene Expression Profile; Gene Fusion; Generations; Genes; Genetic; Genomics; Germ-Line Mutation; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; Heterotopic Ossification; Histone H3; Human; In Vitro; Knock-in Mouse; Missense Mutation; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; N-terminal; NTRK3 gene; Nerve Growth Factor Receptors; Oncogenic; Pathway interactions; Phenotype; Phosphotransferases; Play; Pontine structure; Recurrence; Role; Sampling; Sequence Analysis; Signal Transduction; Structure; Syndrome; Testing; Therapeutic; Xenograft procedure; age group; bone morphogenetic protein receptors; cell type; combinatorial; comparative; design; experience; fusion gene; genome-wide; implantation; improved; in vivo; inhibitor/antagonist; medulloblastoma; mouse model; progressive myositis ossificans; public health relevance; receptor; response; small hairpin RNA; tumor; tumorigenesis

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.

描述（由申请人提供）：成人或儿童的胶质母细胞瘤在很大程度上仍然无法治愈。虽然两个年龄段的神经胶质瘤都针对共同的通路，但每个通路中特定突变的频率在不同年龄组之间有所不同。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以弥漫性内在脑桥胶质瘤（DIPG）的形式出现在脑干中，这种疾病几乎只发生在儿童中。我们小组和其他人的最新研究表明，不同年龄组的神经胶质瘤的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 突变是儿科疾病所特有的，与非脑干儿科胶质母细胞瘤相比，DIPG 的频率和特异性突变存在显着差异。因此，胶质母细胞瘤是多种途径协同突变的结果，其中一些是成人和儿童疾病所共有的，而另一些则是特定发育背景所独有的。在我们未发表的对 112 例儿童高级神经胶质瘤（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 ACVR1 的体细胞激活错义突变，但在非脑干高级神经胶质瘤中没有，这在脑干发育的背景下显示出独特的选择优势。我们还鉴定了涉及三个神经营养素受体 (NTRK) 基因和五个不同 N 末端融合伙伴的激酶结构域的基因融合。这些融合在 40% 的三岁以下儿童非脑干高级神经胶质瘤中发现，而在 DIPG 和年龄较大儿童的非脑干高级神经胶质瘤中出现频率较低。其他人最近的研究也发现儿童低级别胶质瘤和成人胶质母细胞瘤中存在 NTRK 融合。因此，这些改变在多种发育环境中的神经胶质瘤发生中发挥作用。该应用研究了特定突变如何提供选择性优势并在选定的发育环境中促进肿瘤发生，还探索了 PI3K 信号传导的贡献，该信号在所有年龄组的神经胶质瘤中都被破坏。充分了解这些突变的转化机制和下游影响对于这些致命疾病的选择性治疗的明智设计至关重要。