Glioblastomas are extremely complex and malignant neoplasms. We have taken several approaches to understand and identify, at a molecular level, the underlying mechanisms that translate into the malignant behavior of these tumors. 1. Loss of heterozygosity of several markers on chromosomes 17 and 10 was detected in a significant number of glioblastomas. The p53 gene was deleted and/or mutated in 75% of the tumors with gene losses on chromosome 17. Deletion mapping studies on chromosome 17 suggested the presence of another potential tumor suppressor gene distinct from the p53 gene. 2. Immunohistochemical analysis of the p53 protein showed a heterogeneous pattern of subcellular compartmentalization in glioblastomas. Tumors with one single wild type allele of p53 and tumors with one wild type and one mutant allele of p53 and gene losses on chromosome 17p distal to p53 show increased cytoplasmic and/or nuclear accumulation of p53. Furthermore, tumors with mutations in the same codon of p53 display very different staining patterns. These data suggest that the microenvironment of a particular tumor is important in determining the subcellular localization of p53. 3. Twenty tumors were analyzed for collagenase IV and Timp-2 expression. Both these genes were generally over-expressed in glial tumors compared to the normal human brain. 4. Six matched pairs of primary and recurrent tumors were analyzed for allelic deletions on chromosomes 10 and 17 and other genetic alterations. The data clearly demonstrated additional genetic abnormalities in recurrent tumors, which included amplification of the PDGRF gene, point mutations of the p53 gene and overexpression of collagenase. 5. Analysis of metastatic brain tumors showed chromosome 17p deletions and/or p53 mutations in 60% of the tumors. Our data support the concept that p53 gene alterations may contribute to the metastatic spread in certain types of cancers.
