MOLECULAR GENETICS OF HUMAN ASTROCYTOMA

星形细胞瘤是人类最常见的脑肿瘤。 的事实 这些肿瘤随着生物侵袭性的增加而频繁复发 表明星形细胞瘤是一种进行性疾病 暗淡的前景 恶性星形细胞瘤患者的临床表现反映了我们 了解控制遗传的分子机制， 这种致命的人类癌症的发展。 使用DNA的研究 检测限制性片段长度多态性（RFLP）的探针 已经表明，染色体10和17上的特定位点经常被 在恶性星形细胞瘤患者中丢失，提示存在 星形细胞瘤进展中重要的隐性癌基因。 整体 这项研究计划的目的是确定靶基因， 基因突变导致星形细胞瘤进展 这一目标将是 沿着沿着几条调查的途径。 首先，RFLP 恶性星形细胞瘤患者的分析将使用 10号和17号染色体上的多态性DNA标记， 定义越来越小的删除，最终将解决 与这些肿瘤有关的隐性癌基因的位置。 这 分析将通过使用每个手臂的DNA标记来扩展。 人类常染色体发现新的染色体丢失区域， 其他隐性癌基因。 第二，表达和结构 编码人肿瘤抗原p53的基因将在 恶性星形细胞瘤，以确定p53基因是否是靶点 在这些肿瘤中经常发现的染色体17 p缺失。 第三，将检查星形细胞瘤的DNA中ras基因突变， 验证ras基因激活是一个早期事件的假设， 星形细胞瘤进展。 最后，阶段特异性的人星形细胞瘤细胞 将利用10号染色体上基因座的RFLP探针开发品系 和17个作为肿瘤细胞的标记物。

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.