GENOMIC ANALYSIS OF MEDULLOBLASTOMAS

髓母细胞瘤的基因组分析

• 批准号: 7115867
• 负责人: SCOTT Loren POMEROY
• 金额: $ 74.33万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115867
• 关键词: Internet; biological signal transduction; biomarker; children; clinical research; gene expression profiling; gene mutation; human subject; immunocytochemistry; medulloblastoma; microarray technology; molecular biology information system; neoplasm /cancer classification /staging; neoplasm /cancer genetics; neoplasm /cancer therapy; neoplastic growth; pediatric neoplasm /cancer; polymerase chain reaction; prognosis; time resolved data

DESCRIPTION (provided by applicant): Recently, DNA oligonucleotide microarray gene expression analysis has been used to define molecular profiles of medulloblastomas, the most common malignant brain tumors of childhood (Pomeroy et al., 2002). Medulloblastomas were found to be molecularly distinct from other CNS embryonal tumors, and their histological subtypes had unique and functionally significant gene expression patterns. Gene expression profiles were highly predictive of response to therapy, predicting survival in a retrospective analysis with much greater accuracy than current clinical staging criteria or single marker gene outcome predictors. These results must now be prospectively validated before molecular markers can be used for risk stratification in future clinical trials. The experiments of this proposal are correlative biological studies of Phase III medulloblastoma therapy trials of the Children's Oncology Group (COG), designed to optimize and validate prognostic molecular markers. In Specific Aim 1, a multi-molecular outcome predictor, based on gene expression profiles (Affymetrix Human Genome U133 arrays) of tumors from 500 children treated in COG medulloblastoma trials over the next 5 years, will be optimized, validated and developed for "real time" analysis in the context of future clinical trials. In Specific Aim 2, the gene expression database will be used to develop a molecular taxonomy, identifying subclasses of medulloblastomas defined by the expression profiles of molecular signaling pathways that promote tumorigenesis. Gene expression will be linked to oncogenic genomic mutations in Specific Aim 3, by combining expression profiling with genome-wide mutation analysis obtained from DNA BAC clone (Spectral Genomics) microarray-based comparative genomic hybridization. In achieving these Aims, we will create a comprehensive medulloblastoma gene expression and mutation database that is linked to clinical outcome of a large and well-characterized cohort of children. The data will hosted on the website of the NCI/NINDS Glioma Molecular Diagnostic Initiative that is being developed by Howard Fine of the NCI/NINDS Neuro-Oncology Branch and the NIH Bioinformatics group, so that investigators throughout the world can have free access to the molecular and clinical database generated by this project.

描述（由申请人提供）：最近，DNA寡核苷酸微阵列基因表达分析已用于定义髓母细胞瘤的分子特征，髓母细胞瘤是最常见的儿童期恶性脑肿瘤（Pomeroy等，2002）。发现髓母细胞瘤与其他CNS胚胎肿瘤有分子不同，其组织学亚型具有独特且功能意义的基因表达模式。基因表达谱是高度预测对治疗反应的高度预测，在回顾性分析中，其准确性比当前的临床分期标准或单个标记基因结果预测因子更高。现在，必须在将来的临床试验中使用分子标记来进行风险分层之前，必须对这些结果进行前瞻性验证。该提案的实验是对儿童肿瘤学组（COG）的III期髓母细胞瘤治疗试验的相关生物学研究，旨在优化和验证预后分子标记。在特定目标1中，基于未来5年中COG髓母细胞瘤试验中接受的500名儿童的基因表达谱（Affymetrix人基因组U133阵列）的多分子结果预测因子将在未来临床试验的背景下在未来的临床试验中进行优化，验证，用于实时验证，用于实时验证和开发。在特定的目标2中，基因表达数据库将用于开发分子分类学，确定由延迟肿瘤发生的分子信号通路的表达谱所定义的髓母细胞瘤的亚类。基因表达将通过将表达分析与从DNA BAC克隆（光谱基因组学）微阵列基于微阵列的比较基因组杂交相结合，将基因表达与特定目标3中的致癌基因组突变有关。在实现这些目标时，我们将创建一个综合的髓母细胞瘤基因表达和突变数据库，该数据库与大型且特征良好的儿童的临床结果相关联。该数据将在NCI/NINDS神经胶质瘤分子诊断计划的网站上托管，该计划由NCI/NINDS神经肿瘤学分支机构和NIH生物信息信息学组开发，因此，全世界的研究人员可以随意访问该项目的分子和临床数据库。