Molecular Genetics of Gliomagenesis: Progression to glioblastoma multiforme

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GBM is characterized by dense cellularity, high proliferation indices, endothelial proliferation and focal necrosis. At least source of the mitogenic effect is deregulation of the p16-cdk4-cyclin D1-pRb pathway of cell-cycle control. The vast majority, if not all, GBM have alterations of this system.

Chromosome 10p loss is a frequent finding in GBM, occurring in 60-95% of GBMs but only rarely in anaplastic astrocytomas. Attempts to identify this tumor suppressor gene by deletion mapping, however, have been hampered by the observation that, in most cases, the entire chromosome is lost. The gene on the long arm may map to band q25 30-32.

EGFR is a transmembrane receptor tyrosine kinase, whose ligands include EGF and TGF-alpha. The EGFR gene is the most frequently amplified oncogene in astrocytic tumors, being amplified in approximately 40% of all GBM 29 but in few anaplastic astrocytomas. Those GBMs that exhibit EGFR gene amplification have almost always lost genetic material on chromosome 10. Approximately one-third of those GBM with EGFR gene amplification also have specific EGFR gene rearrangements, which produce truncated molecules similar to the v-erbB oncogene. These truncated receptors are capable of conferring dramatically enhanced tumorigenicity to GBM cells. Less commonly amplified oncogenes include N-myc, gli, PDGF-a receptor, c-myc, myb, K-ras, CDK4 and MDM2.

A host of angiogenic growth factors and their receptors are found in GBMs. For example, VEGF and PDGF are expressed by tumor cells while their receptors, flk-1 and flt-1 for VEGF and the PDGF b-receptor for PDGF, are expressed on endothelial cells. VEGF and its receptors, in particular, appear to play a major role in GBM. A link between p53 and tumor angiogenesis has been suggested by the observations that some mutant p53 molecules can enhance VEGF expression and that wild-type p53 regulates the secretion of a glioma-derived angiogenesis inhibitory factor.

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