GBM is the most malignant stage of astrocytoma, with survival times of less than 2 years for most patients. These tumors are characterized histologically by dense cellularity, high proliferation indices, endothelial proliferation, and focal necrosis. The highly proliferative nature of these lesions is no doubt the result of multiple mitogenic effects. As mentioned above, at least one such 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, whether inactivation of p16 or pRb or overexpression of cdk4 or cyclin D1.

Chromosome 10 loss is a frequent finding in GBM, occurring in 60% to 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. On the other hand, there is probably a second tumor-suppressor gene on the short arm, and one study has postulated that a third locus may exist on the long arm, near the centromere.

EGFR is a transmembrane receptor tyrosine kinase whose ligands include EGF and transforming growth factor- alpha. The EGFR gene is the most frequently amplified oncogene in astrocytic tumors, being amplified in approximately 40% of all GBM but in few anaplastic astrocytomas. Those GBMs that exhibit EGFR gene amplification have almost always lost genetic material on chromosome 10. GBMs with EGFR gene amplification display overexpression of EGFR at both the mRNA and protein levels, suggesting that activation of this growth signal pathway is integral to malignant progression to GBM. 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. The downstream targets of EGFR activation in GBMs are not well defined, but EGFR is most likely involved in a cascade that facilitates mitogenesis in tumor cells. Less commonly amplified oncogenes include N- myc, gli, PDGF- alpha receptor, c- myc, myb, K- ras, CDK4, and MDM2, some of which have been discussed above.
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As mentioned above, one of the hallmarks of GBM is endothelial proliferation. 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 beta-receptor for PDGF, are expressed on endothelial cells. VEGF and its receptors, in particular, appear to play a major role in GBM angiogenesis. A paracrine mechanism has been suggested in which VEGF is secreted by tumor cells and bound by the VEGF receptors on endothelial cells. VEGF is preferentially upregulated by tumor cells surrounding regions of necrosis, perhaps as a result of necrosis-induced hypoxia, since hypoxia can upregulate VEGF. 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.

Human brain tumors have molecular alterations characteristic of each type of tumor and of most stages of progression. For instance, the formation of grade II astrocytoma involves inactivation of the p53 tumor-suppressor gene on chromosome 17p, as well as PDGF overexpression, loss of a putative tumor-suppressor gene on chromosome 22q, and the expression of various molecules that facilitate tumor invasion. The transition from astrocytoma to anaplastic astrocytoma is associated with alterations of the critical cell-cycle regulatory pathway that includes p16, cdk4, cyclin D1, and Rb, as well as a putative tumor suppressor gene on chromosome 19q. Finally, progression to GBM involves loss of a at least one putative tumor-suppressor gene on chromosome 10, amplification of the EGFR gene and the expression of angiogenic factors such as VEGF. Furthermore, molecular genetic analysis has been used to identify subsets of astrocytomas. For instance, one type of GBM, characterized by p53 gene mutations, is more common in younger patients and may be associated with slower progression from lower-grade astrocytoma; another type of GBM, characterized by EGFR gene amplification, is more common in older patients and may be associated with more rapid progression or de novo growth.

For the less common gliomas and for other primary tumors such as medulloblastomas, molecular genetic studies have defined only isolated genetic alterations. For meningiomas and schwannomas, the NF2 gene has been clearly implicated, although other genetic alterations must underlie the formation of some meningiomas as well. For those tumors associated with hereditary tumor syndromes, such as the SEGAs in TS and the hemangioblastomas in VHL, the same genes appear responsible for the syndromes when mutated in the germline, and for sporadic tumors when mutated on a somatic basis. At the present time, however, these molecular data are incomplete. Once the molecular pathways are completely understood, such knowledge will no doubt contribute to the development of more effective therapies for many of these tumors.

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