This proposal is approached from the perspective that cancer is a dynamic process which occurs as a result of an accumulation of dominant (activating) and recessive (loss of suppression) genetic alterations. We have applied this perspective to the investigation of the development of central nervous system (CNS) cancer in attempt to define those genes whose alteration are causally involved in the development of this type of neoplasia. The long-term objective of this investigation is to provide genetic compensation for such alterations to determine whether compensation results in suppression of cancer cell phenotypes in in vitro and in vivo model systems. To establish a basis for such experimentation, we are currently involved In the CNS tumor characterization of alterations to three genes. Specifically, these characterizations involve intragenic deletions of amplified epidermal growth factor receptor gene, base substitution (point mutation) of the p53 gene, and deletion of the interferon alpha and beta genes. In addition to these genes, our preliminary data suggest the existence of a novel tumor suppressor gene on chromosome l0 whose loss is essential to the attainment of high-grade CNS tumor malignancy. We are currently working and propose investigations directed towards the identification and isolation of this gene. Execution of the program of research proposed herein will result in significant basic and clinical science contributions as a consequence of information obtained concerning the functional and biological effects of specific gene mutations in CNS tumors.
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