Malignant gliomas are the most common human brain tumors. He has clarified some of the genetic events that underlie the formation of these tumors, but a number of genes involved in glioma tumorigenesis have not yet been cloned. Of the various glioma-related tumor suppressor loci, the chromosome 19q locus is the only one that is deleted in all three major subtypes of malignant diffuse glioma, suggesting that this gene encodes a critical glial growth regulatory protein. Chromosome 19q deletions are common, with allelic loss estimated to occur in approximately 6000 new gliomas each year in the United States. His mapping of the chromosome 19q tumor suppressor gene over the past few years suggests that the gene lies in band 19q 13.3 telomeric to the marker D19S412 and centromeric to the marker STD. He has cloned this candidate region and has further localized the gene to an approximately 200 kb BAC-PAC contig just centromeric to STD. Gene identification approaches to this region have yielded a number of partial coding sequences. To identify and characterize the chromosome 19q glioma tumor suppressor gene, therefore, he proposes: 1) to complete identification of candidate genes, using approaches such as exon trapping, cDNA selection; 2) to identify glioma-specific alterations, using mutation detection techniques such as single strand conformation polymorphism (SSCP) analysis; 3) to define the mutational spectrum of the gene in different types of primary gliomas using SSCO. If the gene is cloned within the proposed funding period, he then proposes: 1) to begin characterization of expression of the 19q gene, including evaluation of the protein encoded by the 10q gene, by generating specific antibodies for Western blotting and immunohistochemistry; and 2) to identify other proteins that interact with the product of the chromosome 19q gene, using immunoprecipitation and yeast two-hybridy screening The identification and characterization of the chromosome 19q glioma tumor suppressor gene will contribute towards understanding a critical step in human glial tumorigenesis and may eventually lead to improved treatment for these malignant tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-PTHB (02))
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Jacobs, Tom P
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Massachusetts General Hospital
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