The long-term goal of this program is to use cytogenetic and molecular genetic approaches to understand mechanisms of growth control of human gliomas. During the past several years cytogenetic analysis and allelotyping of tumors of all grades and histologic types have been used to determine chromosomes and chromosomal regions which are critical to the development and progression of these tumors. We have demonstrated that the most prevalent cytogenetic alterations in glioblastoma are gains of chromosome 7, losses of chromosomes 10 and 9p and the presence of double minute chromosomes (DMs). The majority of tumors with DMs have amplification of the epidermal growth factor receptor gene, loss of 9p is probably associated with deletion of the Multiple Tumor Suppressor 1 (MTS1) gene, and most tumors with 17p loss have mutations of the TP53 gene but the relevant genes on chromosomes 7 and 10 remain unknown. The specific region of chromosome 10 which is deleted in the majority of glioblastomas has been localized by deletion mapping to 10q25 as defined by loci D10S587 to D10S216, a region estimated to be less than 2 centimorgans. We are presently characterizing YAKs in this region and evaluating a series of glioma xenografts for homozygous deletions in this region to allow us to eventually isolate and characterize the relevant gene on this chromosome. The other tumor which we are studying is medulloblastoma. We have demonstrated that subsets of these tumors have loss of chromosome 17p and that a small number of cases have p53 gene mutations and c-myc gene amplification. We are presently narrowing the region of 17p deletion and are evaluating the prognostic significance of these 3 parameters.
