GENETIC AND BIOLOGIC STUDIES OF 1P AND 19Q IN GLIOMAS

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Alterations of chromosomes 1 and 19 are frequent events in human gliomas and have recently been suggested to be associated with chemotherapeutic response and prolonged survival in anaplastic oligodendrogliomas. However, the genes on these chromosome arms that are altered in gliomas and potentially associated with chemotherapeutic response and survival have not been identified. Furthermore, the exciting response and survival data have not been confirmed in an appropriately-treated, prospectively-collected cohort of patients nor have these clinical correlations been translated to lower grade oligodendrogliomas or other glial tumors. We have made considerable progress in mapping the genomic location of the 19q gene and have identified several genes in this region. In addition, we have assembled several prospectively-collected cohorts of patients to confirm and extend the clinical observations of Caimcross et al. In this application, we propose to 1) Complete the identification of the 19q gene (or genes) involved in the development of gliomas, 2) Begin an evaluation of the function of the 19q gene (or genes), 3) Finely map the minimal 1p deletion region in gliomas, to begin to identify the gene (or genes) on 1p involved in the development of gliomas, and 4) To perform clinical-translational studies designed to validate the postulated predictive value of 1p/19q alterations, to determine if alterations of the specific genes involved have similar associations, and to extend the associations to lower grade tumors and to tumors of different glial lineage. Thus, this project will identify and begin to study the function of the 19q gene, map the 1p deletion region, and further define the clinical significance of the 1p and 19q alterations. The overall result of this project will be an initial understanding of the genetics and biology of the 19q and 1p genes as well as the development of a combined histologic and genotypic assessment of gliomas that could potentially be used to stratify patients for therapy.