Genome-wide promoter methylation profiling of glioma

神经胶质瘤的全基因组启动子甲基化分析

• 批准号: 7675448
• 负责人: Albert Lai
• 金额: $ 13.65万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675448
• 关键词: Anaplastic astrocytoma; Antibodies; Area; Astrocytoma; Avastin; Azacitidine; Bioinformatics; Biology; Brain; Brain Neoplasms; Candidate Disease Gene; Cell Line; Clinic; Clinical; Clinical Trials; Collection; Correlative Study; CpG Islands; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Data Set; Databases; Dysmyelopoietic Syndromes; Enrollment; Environment; Epigenetic Process; Freezing; Gene Expression; Genes; Genetic; Genetic Transcription; Glioblastoma; Glioma; Goals; Image; Laboratories; Lead; Loss of Heterozygosity; Maintenance; Malignant - descriptor; Malignant neoplasm of brain; Mentors; Methods; Methylation; Molecular; Molecular Profiling; Newly Diagnosed; O(6)-Methylguanine-DNA Methyltransferase; O-(6)-methylguanine; Oligonucleotides; Oncologist; Outcome; Patients; Pattern; Principal Investigator; Procedures; Protocols documentation; Radiation; Radiation therapy; Recurrence; Research; Research Personnel; Resources; Role; Safety; Sampling; Stratification; Subgroup; Therapeutic; Tissue Banks; Tissue Sample; Tissues; Training Programs; Tumor Bank; Tumor Tissue; Vascular Endothelial Growth Factors; anticancer research; base; bevacizumab; design; epigenomics; experience; genome-wide; improved; insight; irinotecan; neoplastic cell; neuro-oncology; novel; novel therapeutic intervention; professor; programs; promoter; prospective; response; standard of care; temozolomide; tumor

DESCRIPTION (provided by applicant): The proposed five-year training program is designed to provide the principal investigator with the background in microarray-based genome-wide epigenomic profiling directed towards translational brain cancer research. As an Assistant Professor, the PI is a clinically active neuro-oncologist with designated laboratory space. This training program will enable him to enter a new area of research that is directly synergistic with his clinical efforts as a co-principal investigator on a recently opened UCLA/Genentech clinical trial (target enrollment of 70 patients) evaluating the use of bevacizumab (Avastin) in combination with temozolomide and radiation for patients with newly-diagnosed glioblastoma. Critical determinants in his training program are the mentor, Dr. Stan Nelson, access to the UCLA Neuro-oncology database, and active support of the UCLA brain tumor research environment. Dr. Nelson is a recognized leader in the field of genome-wide array based analysis and has been active in large-scale genetic characterization of patient glioblastoma tissue in the UCLA Neuro-oncology database, a large clinically annotated collection of patient tissue, cell lines, and radiographic images. The potential for powerful correlative studies harnessing this database have been realized by a large number of recent studies from the UCLA group. The overall goal of the research plan is based on the recent discovery that glioblastoma patients whose tumors have O(6)-Methylguanine DNA methyltransferase (MGMT) promoter methylation demonstrate better survival and response to temozolomide (TMZ). This finding emphasizes the importance of aberrant methylation in brain cancer. We hypothesize that genome-wide methylation profiling of glioma will lead to the discovery of novel methylated genes and signatures of coordinately methylated genes, and we demonstrate the feasibility of using differential methylation hybridization (DMH) to achieve these goals. The specific aims are: 1) to understand the role of promoter methylation in astrocytoma transformation by comparing genome-wide methylation profiles of low grade astrocytomas, anaplastic astrocytomas, primary and secondary glioblastomas, and normal brain samples, 2) to determine genome-wide methylation, gene expression, and loss of heterozygosity (LOH) profiles associated with response to a novel upfront therapy combining bevacizumab with radiation therapy and TMZ, 3) to examine the role of DNA methyltransferase 1 (DNMT1) in glioblastoma methylation by profiling genome-wide methylation changes in glioblastoma cell lines resulting from pharmacologic or genetic modulation of DNMT1 activity. The overall goal of this proposal is to improve therapeutic outcomes for glioma patients by developing personalized approaches based on prospective molecular characterization of tumor samples.

描述（由申请人提供）：拟议的五年培训计划旨在为主要研究者提供基于微阵列的全基因组表观基因组分析的背景知识，该背景知识针对转化型脑癌研究。作为助理教授，PI是临床活跃的神经肿瘤学家，拥有指定的实验室空间。该培训计划将使他能够进入一个新的研究领域，该领域与他作为最近开放的UCLA/Genentech临床试验（目标招募70名患者）的共同主要研究者的临床工作直接协同，该临床试验评估了贝伐单抗（Avastin）与替莫唑胺和放射联合用于新诊断的胶质母细胞瘤患者。在他的培训计划的关键决定因素是导师，斯坦纳尔逊博士，访问加州大学洛杉矶分校神经肿瘤学数据库，并积极支持加州大学洛杉矶分校脑肿瘤研究环境。纳尔逊博士是基于全基因组阵列分析领域公认的领导者，并一直活跃于UCLA神经肿瘤学数据库中胶质母细胞瘤患者组织的大规模遗传表征，该数据库是患者组织、细胞系和放射影像学图像的大型临床注释集合。利用该数据库进行强有力的相关研究的潜力已经被加州大学洛杉矶分校小组最近的大量研究所实现。研究计划的总体目标是基于最近的发现，即肿瘤具有O（6）-甲基鸟嘌呤DNA甲基转移酶（MGMT）启动子甲基化的胶质母细胞瘤患者表现出更好的生存率和对替莫唑胺（TMZ）的反应。这一发现强调了异常甲基化在脑癌中的重要性。我们假设，全基因组甲基化分析胶质瘤将导致发现新的甲基化基因和协调甲基化基因的签名，我们证明了使用差异甲基化杂交（DMH）来实现这些目标的可行性。具体目标是：1）通过比较低级别星形细胞瘤、间变性星形细胞瘤、原发性和继发性胶质母细胞瘤和正常脑样品的全基因组甲基化谱，了解启动子甲基化在星形细胞瘤转化中的作用，2）确定与对将贝伐单抗与放射疗法和TMZ组合的新型前期疗法的应答相关的全基因组甲基化、基因表达和杂合性缺失（洛）谱，3）通过分析胶质母细胞瘤细胞系中由DNMT 1活性的药理学或遗传学调节引起的全基因组甲基化变化来检查DNA甲基转移酶1（DNMT 1）在胶质母细胞瘤甲基化中的作用。该提案的总体目标是通过基于肿瘤样本的前瞻性分子表征开发个性化方法来改善神经胶质瘤患者的治疗结果。