MOLECULAR GENETICS OF HUMAN ASTROCYTOMA

人类星形细胞瘤的分子遗传学

• 批准号: 3460003
• 负责人: DANIEL WEBSTER FULTS
• 金额: $ 9.42万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3460003
• 关键词: astrocytoma; autosomal recessive trait; chromosome disorders; chromosome translocation; genetic markers; human genetic material tag; human tissue; messenger RNA; molecular oncology; neoplasm /cancer genetics; nucleic acid probes; nucleic acid sequence; oncogenes; restriction fragment length polymorphism; restriction mapping; tissue /cell culture; tumor antigens

Astrocytoma is the most common brain tumor in humans. The fact that these tumors recur frequently with increased biological aggressiveness indicates that astrocytoma is a progressive disease. The dismal outlook for patients with malignant astrocytoma reflects shortcomings in our understanding of the molecular mechanisms that govern the genesis and progression of this lethal form of human cancer. Studies using DNA probes that detect restriction fragment length polymorphisms (RFLP's) have shown that specific loci on chromosomes 10 and 17 are frequently lost in patients with malignant astrocytomas, suggesting the presence of recessive oncogenes important in astrocytoma progression. The overall objective of this research proposal is to identify genes that are targets for mutations that drive astrocytoma progression. This objective will be approached along several avenues of investigation. First, an RFLP analysis of malignant astrocytoma patients will be carried out using polymorphic DNA markers for loci on chromosomes 10 and 17 in order to define increasingly smaller deletions that will ultimately resolve the location of recessive oncogenes implicated in these tumors. This analysis will be extended by using DNA markers for each arm of every human autosome to uncover new areas of chromosome loss that might harbor additional recessive oncogenes. Second, the expression and structure of the gene encoding the human tumor antigen p53 will be examined in malignant astrocytomas to determine whether the p53 gene is the target for the chromosome 17p deletions found frequently in these tumors. Third, DNA from astrocytomas will be examined for ras gene mutations to test the hypothesis that ras gene activation is an early event in astrocytoma progression. Finally, stage-specific human astrocytoma cell lines will be developed utilizing RFLP probes for loci on chromosomes 10 and 17 as markers for tumor cells.

星形细胞瘤是人类最常见的脑瘤。事实是， 随着生物侵袭性的增加，这些肿瘤经常复发。 说明星形细胞瘤是一种进行性疾病。黯淡的前景 对恶性星形细胞瘤患者的治疗反映了我们在 对控制疾病发生和发展的分子机制的理解 这种致命的人类癌症的进展。使用DNA进行研究 检测限制性片段长度多态(RFLP)的探针 已经表明，10号和17号染色体上的特定基因座经常 在恶性星形细胞瘤患者中丢失，提示存在 隐性癌基因在星形细胞瘤进展中的重要作用。整体而言 这项研究计划的目的是识别作为靶点的基因 导致星形细胞瘤进展的突变。这一目标将是 通过几种调查途径进行调查。首先，一个RFLP 恶性星形细胞瘤患者的分析将使用 10号和17号染色体上座位的多态DNA标记 定义越来越小的删除，以最终解决 与这些肿瘤有关的隐性癌基因的位置。这 将通过对每个人的每一只手臂使用DNA标记来扩展分析 人类常染色体发现可能存在的新的染色体丢失区域 附加的隐性致癌基因。第二，语言的表达和结构 编码人类肿瘤抗原P53的基因将在 恶性星形细胞瘤确定p53基因是否是靶点 对于这些肿瘤中常见的染色体17p缺失。 第三，将对星形细胞瘤的DNA进行ras基因突变检查，以 检验ras基因激活是早期事件的假设。 星形细胞瘤进展。最后，特定阶段的人类星形细胞瘤细胞 将利用RFLP探针开发10号染色体上的基因座品系 17作为肿瘤细胞的标志物。