Cooperating Pathways in Gliomagenesis

神经胶质瘤发生中的合作途径

基本信息

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
项目类别：
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

项目摘要

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 In our unpublished genomic sequencing analysis of 112 pediatric high-grade gliomas, including 54 DIPGs, we identified somatic activating missense mutations in the BMP receptor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.

描述（由申请人提供）：成人或儿童引起的胶质母细胞瘤仍然无法治愈。而两个年龄段的胶质瘤靶向公共途径，而年龄组之间每个途径中特定突变的频率也有所不同。尽管小儿和成人胶质母细胞瘤具有相似的组织病理学特征，但大约一半的小儿胶质母细胞群在脑干中出现，因为弥漫性固有的pontine gliomas（DIPGS），这种疾病几乎完全发生在儿童中。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有显着差异。最值得注意的是，与非脑干小儿胶质母细胞瘤相比，频繁的组蛋白H3突变是针对小儿疾病的特异性特异性的，在DIPG中的频率和特异性突变差异很大。因此，胶质母细胞瘤是由于多种途径合作的突变而产生的，其中一些是成人和小儿疾病之间共享的，而另一些则是特定发育环境所特有的。在我们对112个小儿高级神经胶质瘤的未发表的基因组测序分析中，包括54个DIPG，我们在32％的DIPG中鉴定了BMP受体ACVR1中的体细胞激活失误突变，但在非脑干系统高级胶质瘤中却没有显示出独特的选择性优势，在发育中的大脑中显示出独特的选择优势。我们还确定了涉及三种神经营养蛋白受体（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。这些融合在三岁以下的儿童的40％的非脑干高级神经胶质瘤中发现，在较低的DIPG和非Brainstem高级神经胶质瘤中，来自大儿童的频率较低。来自其他人的最新研究还确定了小儿低级神经胶质瘤和成人胶质母细胞瘤的NTRK融合。因此，这些改变在多种发育环境中的神经胶质作用中起作用。该应用调查了特定的突变如何提供选择性优势，并在某些发育环境中有助于肿瘤发生，还探讨了PI3K信号的贡献，PI3K信号传导在所有年龄段的神经胶质瘤中都受到破坏。对这些突变的转化和下游效应的机制充分理解对于这些致命疾病的选择性治疗的知情设计至关重要。