MOLECULAR CYTOGENETICS--PEDIATRIC CNS TUMORS

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Cytogenetic and molecular techniques have advanced our knowledge of the biologic basis of cancer, particularly in the pediatric neoplasms. Information regarding pediatric tumors of the central nervous system has been limited due to technical problems and United access to specimens. For these reasons we propose a molecular and cytogenetic evaluation of pediatric CNS tumors. In this program, we will prepare karyotypes from an extended series of pediatric brain tumors. Our studies will include analysis of direct preparations from tumors, and short term tissue culture of tumor specimens and peripheral blood. We will examine loss of alleles on 17p in CNS tumors to narrow the region which we propose contains a locus critical to the development of PNETS. We will further define and narrow the region of 22q implicated as containing a tumor suppressor locus for rhabdoid or a typical teratoid tumors of the brain. Mutation-prone "hot spots" in the p53 locus of malignant tumors will be sequenced to assess the frequency of mutations in this locus in pediatric tumors of the CNS. We will develop sequence-based diagnostic assays for detection of i(17q) and monosomy 22 in clinical material to aid in the diagnosis of these subsets of tumors. Thus, DNA sequences identified from our studies will be applied to detection of the relevant abnormality in clinical samples by PCR analysis and interphase fluorescence in situ hybridization. Finally, we will correlate the findings of these cytogenetic and molecular assays with clinical outcome and immunophenotyping. This will involve comparisons of the cytogenetic and molecular findings with clinical characteristics and specialized immunohistochemical studies. As we begin to understand the functional consequences of genomic alterations, by identifying the genes involved and the mechanisms by which they exert their effect, we will be able to translate this information into improvements in diagnosis and therapy.