Identification of Genetic Alterations Responsible for Primary GBM Clonal Evoluti

原发性GBM，占人类GBM的90%以上，在没有先前临床表现的情况下迅速或从头发展。 疾病大规模的基因组分析极大地促进了胶质瘤的定义 景观和数据集（TCGA）已经使得GBM能够基于它们的基因组划分为子类， 转录组学和信号转导模式。可悲的是，尽管这些见解的遗传学的 尽管神经外科、放射治疗和化学治疗的进步， 显著与继发性GBM不同，获得的遗传改变的顺序和时间 在原发性GBM中仍有待阐明，更重要的是，这些获得性遗传改变是如何发生的？ 导致这种毁灭性疾病的侵袭性和恶性表型还没有得到很好的理解。 项目2将利用p53“^”（R）模型，该模型模拟成人原发性GBM的发病机制， 甚至在神经胶质瘤形成的最早阶段也有高度的核变性。工作假设是， 最早的病变很可能包括少量的致癌突变或扩增 使靶细胞增殖超过正常水平。增强的增殖与 增加基因组不稳定性的突变可能导致进一步的基因组损伤，包括肿瘤细胞的丢失。 抑制基因（例如Pten），进一步放大增殖。在具体目标1中，我们将检验假设 p53缺陷促进SVZ干/祖细胞中关键遗传改变的积累， 导致克隆扩增和初级GBM形成。遗传改变的获得，如 染色体19（携带Pten）导致快速生长和GBM进展。具体目标2将监测 这些发展中的肿瘤对标准化疗/放疗的反应，目的是确定 遗传改变导致对治疗的抗性，这是GBM的一个共同特征。第3章测试 假设胶质瘤的早期阶段代表了最好的治疗机会， 更有限的克隆异质性。病变内异质性克隆的存在导致肿瘤 适应性和复发是胶质瘤治疗耐药的重要因素。由于能力 MRI-PRM（在项目3中开发），用于检测大脑中稍后将形成对比的区域 增强病变，我们将使用MRI通过精确的检测来识别胶质瘤形成中的早期遗传改变， 用于基因组分析的早期肿瘤的立体定位活检。我们预测，靶向抑制的关键 神经胶质瘤起始信号传导途径将通过防止复发而显著提高结果（存活）。

Primary GBM, accounting for over 90% of human GBMs, develops rapidly or de novo with no prior clinical disease. Large-scale genomic analyses have contributed greatly to the definition of the overall glioma landscape and datasets (TCGA) have enabled the division of GBMs into subclasses based on their genomic, transcriptomic, and signal transduction patterns. Sadly, despite these insights into the genetics of the disease and advances in neurosurgery, radiation and chemotherapy, its dismal prognosis has not changed significantly. Unlike secondary GBM, the order and the timing of the genetic alterations that are acquired remain to be elucidated in primary GBM, and more importantly, how these acquired genetic alterations contribute to aggressive and malignant phenotypes in this devastating disease aren't well understood. Project 2 will utilize the p53'^^^'(R) model which mimics the pathogenesis of adult onset primary GBM with a high degree of nuclear atypia even in the earliest stages of gliomagenesis. The working hypothesis is that the eariiest lesion most likely comprises a small number of oncogenic mutations or amplifications that enables the targeted cell(s) to proliferate beyond normal means. Enhanced proliferation in conjunction with mutations that increase genomic instability may lead to further genomic lesions, including loss of tumor suppressor genes (e.g. Pten), further amplifying proliferation. In Specific Aim 1, we will test the hypothesis that p53 deficiency facilitates the accumulation of critical genetic alterations in the SVZ stem/progenitor cells leading to clonal expansion and primary GBM formation. Acquisition of genetic alterations such as loss of chromosome 19 (harboring Pten) leads to rapid growth and GBM progression. Specific Aim 2 will monitor the response of these evolving tumors to standard of care chemo/radiation therapy, with the goal of defining genetic alterations that result in resistance to therapy, a common feature of GBM. Specific Aim 3 will test the hypothesis that the early stages of gliomagenesis represent the best therapeutic opportunities due to a more limited heterogeneity of clones. The presence of heterogeneous clones within a lesion leads to tumor adaptivity and recurrence an important contributor to therapeutic resistance in glioma. Due to the ability of MRI-PRM (developed in Project 3) to detect areas within the brain that will later develop a contrast enhancing lesion, we will use MRI to identify early genetic alterations in gliomagenesis through precise stereotaxic biopsy of early stage tumors for genomic analysis. We predict that targeted inhibition of key glioma-initiating signaling pathways will significantly enhance outcomes (survival) by preventing recurrence.