MOLECULAR GENETICS OF HUMAN ASTROCYTOMA

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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.