Identification of Genetic Alterations Responsible for Primary GBM Clonal Evoluti

鉴定导致原发性 GBM 克隆进化的遗传改变

• 批准号: 8510981
• 负责人: Alnawaz Rehemtulla
• 金额: $ 45.18万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-05 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510981
• 关键词: Accounting; Adult; Aneuploidy; Area; Bioinformatics; Biopsy; Brain; Brain Neoplasms; Cells; Characteristics; Chromosomal Gain; Chromosomal Loss; Chromosomal translocation; Clinical; Clonal Expansion; Data Set; Defect; Development; Diagnostic Neoplasm Staging; Disease; Early Diagnosis; Early treatment; Enhancing Lesion; Event; Evolution; Exhibits; Genetic; Genetically Engineered Mouse; Genome; Genomic Instability; Genomics; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; Hereditary Disease; Heterogeneity; Human; Human Chromosomes; Image; Imaging Techniques; Individual; Instruction; Large-Scale Sequencing; Lead; Lesion; Magnetic Resonance Imaging; Malignant Glioma; Modeling; Molecular; Molecular Genetics; Monitor; Mus; Mutation; Nature; Nuclear Atypia; Oncogenic; Operative Surgical Procedures; Outcome; PTEN gene; Pathogenesis; Pathway interactions; Pattern; Penetrance; Periderm; Phase; Probability; Process; Proliferating; Radiation; Radiation therapy; Radio; Receptor Protein-Tyrosine Kinases; Recurrence; Resistance; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissue Banks; Tissues; Treatment Efficacy; Tumor Suppressor Genes; Tumor stage; Work; base; brain cell; chemotherapy; chromosome 19 loss; design; genome wide association study; improved; in vivo; insight; malignant phenotype; mouse model; neurosurgery; novel; outcome forecast; preclinical study; prevent; rapid growth; response; standard of care; stem; therapy resistant; transcriptomics; tumor; tumor growth; Accounting; Adult; Aneuploidy; Area; Bioinformatics; Biopsy; Brain; Brain Neoplasms; Cells; Characteristics; Chromosomal Gain; Chromosomal Loss; Chromosomal translocation; Clinical; Clonal Expansion; Data Set; Defect; Development; Diagnostic Neoplasm Staging; Disease; Early Diagnosis; Early treatment; Enhancing Lesion; Event; Evolution; Exhibits; Genetic; Genetically Engineered Mouse; Genome; Genomic Instability; Genomics; Glioblastoma; Glioma; Gliomagenesis; Goals; Growth; Hereditary Disease; Heterogeneity; Human; Human Chromosomes; Image; Imaging Techniques; Individual; Instruction; Large-Scale Sequencing; Lead; Lesion; Magnetic Resonance Imaging; Malignant Glioma; Modeling; Molecular; Molecular Genetics; Monitor; Mus; Mutation; Nature; Nuclear Atypia; Oncogenic; Operative Surgical Procedures; Outcome; PTEN gene; Pathogenesis; Pathway interactions; Pattern; Penetrance; Periderm; Phase; Probability; Process; Proliferating; Radiation; Radiation therapy; Radio; Receptor Protein-Tyrosine Kinases; Recurrence; Resistance; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissue Banks; Tissues; Treatment Efficacy; Tumor Suppressor Genes; Tumor stage; Work; base; brain cell; chemotherapy; chromosome 19 loss; design; genome wide association study; improved; in vivo; insight; malignant phenotype; mouse model; neurosurgery; novel; outcome forecast; preclinical study; prevent; rapid growth; response; standard of care; stem; therapy resistant; transcriptomics; tumor; tumor growth

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.

占人类GBM的90％以上的初级GBM，迅速发展或从头开始而没有先前的临床 疾病。大规模的基因组分析对整体神经胶质瘤的定义做出了巨大贡献 景观和数据集（TCGA）已根据其基因组将GBMS分为子类别 转录组和信号转导模式。可悲的是，尽管对遗传学的见解 疾病和神经外科，放射和化学疗法的进展，其惨淡的预后没有改变 显著地。与次级GBM不同，获取的遗传改变的顺序和时机 在初级GBM中仍然有待阐明，更重要的是，这些获得的遗传改变了 在这种毁灭性疾病中有助于侵略性和恶性表型。 项目2将利用p53'^^^'（R）模型，该模型模拟了成人发作的初级GBM的发病机理 高度的核亚典现象，即使在神经胶质作用的最早阶段也是如此。工作的假设是 最具痛苦的病变很可能包括少数的致癌突变或放大的病变 使目标细胞能够超越正常均值。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病变，包括肿瘤的丧失 抑制基因（例如PTEN），进一步扩大增殖。在特定目标1中，我们将检验假设 p53缺乏促进了SVZ茎/祖细胞中关键遗传改变的积累 导致克隆扩张和主要GBM形成。获取遗传改变，例如丢失 19染色体（藏有PTEN）导致快速生长和GBM进展。具体目标2将监视 这些不断发展的肿瘤对护理标准化学/放射治疗的反应，目的是定义 遗传改变会导致对治疗的抗性，这是GBM的共同特征。特定目标3将测试 神经胶作用的早期阶段是由于A代表最佳治疗机会的假设 克隆的异质性更有限。病变内的异质克隆的存在导致肿瘤 适应性和复发是神经胶质瘤治疗性抗性的重要促进者。由于能力 MRI-PRM（在项目3中开发）检测大脑内将形成对比的区域 增强病变，我们将使用MRI通过精确确定神经胶质作用的早期遗传改变 早期肿瘤的立体定位活检进行基因组分析。我们预测针对密钥的抑制 胶质瘤发射信号通路将通过预防复发来显着提高预后（存活）。