The long term goal of this laboratory is to determine the molecular basis of the cytogenetic abnormalities which characterize human gliomas and to define the role of these alterations in the genesis and progression of these tumors. During the previous funding period, we have determined that loss of heterozygosity (LOH) for 17p is associated with the TP53 gene mutations, that double minute chromosomes (DMs) are associated with amplification, often with rearrangement, of the epidermal growth factor receptor (EGFR) gene, that loss of 9p is associated with homozygous deletion of the CDKN2 gene, and that loss of all or part of chromosome 10 often reflects deletion or mutation of the PTEN/MMAC1 gene. In the present application we will use these genetic alterations, along with histologic parameters and immunohistochemical markers, to precisely and reproducibly separate glioma patients into prognostic groups and to identify patients who are likely to respond to specific forms of treatment.
In Specific Aim 1 we will test the ability of age of the patient, histologic features, proliferation index, p53 gene mutations, gene amplification, and LOH for 1p, 9p, chromosome 10, and 19q to distinguish between astrocytic and oligodendroglial tumors and to grade tumors within these cytologic groups. We will also use immunohistochemical and biochemical markers to identify patients whose tumors contain antigens or molecular defects which render them susceptible or resistant to specific therapeutic modalities. Since loss of chromosome 10 tumor suppressor genes which are altered in these tumors, including PTEN, DMBT1, and new suppressor genes, particularly on 10p. We believe that these studies will provide accurate classification of brain tumor patients, for the prospective analysis of specific therapeutic regimens. Our goal is to select therapy for individual patients based on immunohistochemical, biochemical, or molecular genetic characteristics of their tumors, and by doing so have the best chance of avoiding resistance and achieving response or even cure in a subset of malignant glioma patients.
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