Malignant gliomas are the most common primary human brain tumor, but their classification remains controversial and effective therapies remain elusive. The common malignant gliomas can be divided into astrocytomas (including the highly malignant glioblastoma multiforme), oligodendrogliomas and mixed gliomas (oligoastrocytomas). Molecular genetic analyses of astrocytomas revealed tumor suppressor loci on chromosomes 9p, 10, 13q, 17p, 19q, and 22q while studies of oligodendrogliomas and mixed gliomas have suggested tumor suppressors on chromosomes 1p and 19q. The chromosome 19q locus is, therefore, the only tumor suppressor gene associated in all three subtypes of malignant diffuse glioma, with estimates suggesting it is involved in approximately 6000 new gliomas each year in the United States. Furthermore, alterations of the 19q locus are unique to glial tumors since other human cancers do not show allelic loss of 19q. Mapping the chromosome 19q tumor suppressor gene suggests that the gene lies telomeric to marker D19S412 and probably centromeric to the marker D19S112. To test the hypothesis that a tumor suppressor gene integral to glioma tumorigenesis lies on chromosome 19q13.3 between the markers D19S219 and D19S112 this application proposes five Specific Aims.
Specific Aim 1 proposes to identify candidate genes in the deleted regions by exon amplification using cosmids that have been mapped to the region. The trapped exons will be used to search available DNA and protein sequence databases and to screen libraries for full-length cDNAs.
Specific Aim 2 will confirm and further define the region suspected to harbor the tumor suppressor gene. This will be accomplished by utilizing DNA from primary gliomas to detect allelic loss of heterozygosity at newly identified polymorphic microsatellite loci within the larger, D19S219--HRC, candidate region.
Specific Aim 3 will identify intermediate-sized deletions and rearrangements, DNA from cultured and primary gliomas will be studied with routine and with pulsed-field gel electrophoresis and Southern blotting, using exons from the candidate region.
Specific Aim 4 will detect tumor-specific mutations, candidate exons or cDNAs will be screened for mutations in primary gliomas using genomic or cDNA-based single strand conformation polymorphism analysis and direct DNA sequencing. And lastly, Specific Aim 5 will define the mutational spectrum of the gene, the genomic structure will be characterized and mutational analysis completed on primary gliomas. Mutations will be correlated with clinical histopathological and other molecular genetic parameters.
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