Glioblastoma Genome Project to Locate Molecular Targets

胶质母细胞瘤基因组计划定位分子靶点

• 批准号: 7098137
• 负责人: GREGORY Joseph RIGGINS
• 金额: $ 67.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-09 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098137
• 关键词: clinical research; gene mutation; genes; genome; glioblastoma multiforme; neoplasm /cancer

DESCRIPTION (provided by applicant): The main goal of this work is to locate and evaluate molecular targets for brain cancers, starting with glioblastoma. This project serves as a pilot for larger cancer re-sequencing projects. We have teamed with the Venter Institute and its associated Joint Technology Center to perform state-of-the-art and low cost sequencing using their SNP detection pipeline. For our first specific aim, we will re-sequence all known kinase domains in the cancer genomes of 30 glioblastomas. Once a kinase domain mutation is detected we expand our analysis to the entire gene in 50 additional glioblastomas and a panel of other brain cancers, including pediatric glioblastomas and medulloblastomas. In our preliminary analysis of the first 40 kinase genes, novel tyrosine receptor kinase mutations were found in FGFR1 and PDGFRA. We have also found additional mutations in PIK3CA in adult and pediatric glioblastoma. In specific aim 2, we propose to create a high-resolution copy number map of our 30 glioblastomas using Digital Karyotyping, so we can evaluate in the same samples point mutations, amplifications and deletions. We have completed Digital Karyotyping in 8 glioblastomas, and previously published on using this powerful technique to find a developmental gene genomic amplification in medulloblastoma. In specific aim 3 we will functionally evaluate the mutations we find with frequency greater than 10%, starting with two kinase mutations we have already found in glioblastoma. We will create a model system of the mutation in cell lines and determine the target of altered phosphorylation and if the cell-cycle, apoptosis and/or invasion are altered. To ensure rapid reporting and integration of our work into larger efforts we propose an online database and reporting for our fourth and final specific aim. Glioblastomas have poor survival and new treatments are needed. Our long-term goal is to choose the best molecular targets from this systematic analysis and determine if inhibition of these new mutations will be a successful therapeutic strategy.

描述（由申请人提供）：这项工作的主要目标是定位和评估脑癌的分子靶标，从胶质母细胞瘤开始。该项目是大型癌症重新测序项目的试点。我们已经与Venter Institute及其相关的联合技术中心合作，使用其SNP检测管道进行最先进的成本测序。对于我们的第一个特定目的，我们将在30个胶质母细胞瘤的癌症基因组中重新序列所有已知的激酶结构域。一旦检测到激酶结构域突变，我们将分析扩展到50个其他胶质母细胞瘤和其他脑癌的小组，包括小儿胶质母细胞瘤和髓母细胞瘤。在我们对前40种激酶基因的初步分析中，在FGFR1和PDGFRA中发现了新型酪氨酸受体激酶突变。我们还发现了成人和小儿胶质母细胞瘤中PIK3CA的其他突变。在特定目标2中，我们建议使用数字核分型创建30个胶质母细胞瘤的高分辨率副本映射，以便我们可以在相同的样品点突变，放大和删除中评估。我们已经完成了8个胶质母细胞瘤中的数字核分型，并以前发表过使用这种强大的技术在髓母细胞瘤中找到发展基因基因组扩增。在特定目标3中，我们将在功能上评估我们发现的频率大于10％的突变，从我们在胶质母细胞瘤中已经发现的两个激酶突变开始。我们将在细胞系中创建一个突变的模型系统，并确定改变磷酸化的靶标，以及细胞周期，凋亡和/或侵袭是否改变。为了确保将工作的快速报告和整合到更大的努力中，我们建议在线数据库，并报告我们的第四个也是最终特定目标。胶质母细胞瘤的生存差，需要新的治疗方法。我们的长期目标是从该系统分析中选择最佳的分子靶标，并确定对这些新突变的抑制是否将是成功的治疗策略。