ETIOLOGY AND PATHOBIOLOGY OF MENINGIOMAS

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Meningiomas, derived from the thin membrane covering the brain and spinal cord, are one of the most common tumors of the central nervous system. Currently, the mechanisms responsible for the initiation and pathology of meningiomas are largely unknown. We propose here a strategy that is designed to not only elucidate the underlying basis for this disease, but also allow the identification of downstream changes in gene expression that could contribute to meningioma aggressivity and chance for recurrence. Our working hypothesis for this proposal is that meningiomas result from loss of function of a "tumor suppressor" gene located on chromosome 22. We call this the meningioma susceptibility locus (msl). The broad, long-term objective of the proposed research is to identify and fully define the function of this candidate tumor suppressor gene, and determine its role in negatively regulating cellular proliferation. Toward that goal we propose to isolate and characterize cDNA clones representing the msl gene, as well as other functionally important genes whose expression is missing/altered in meningiomas relative to their normal precursor, leptomeningeal cells. To do this we have constructed "subtraction" cDNA libraries that are enriched for candidate sequences for the msl gene, by using cultures of primary leptomeningeal cells established in this laboratory together with two meningioma cell lines. Screening of these subtraction libraries with subtracted, leptomeningeal-enriched probes have identified and will continue to provide candidates for the msl gene and others of interest. These cDNA clones will be characterized as follows: (a) chromosomal mapping and analysis of tissue specificity of expression; (b) search for deletions or rearrangements of these sequences in genomic DNA of meningiomas; (c) analysis of RNA from a panel of other brain tumors, particularly those associated with the disorder NF2, to address the proposal that these brain tumors may share a common pathway of transformation; (d) DNA transfection protocols to examine the possible role of these genes in the suppression of cell growth or the induction of differentiation. The ultimate goal is to use information generated on the mechanism of leptomeningeal cell tumorigenesis towards the effective diagnosis, screening and therapy of meningiomas.