Molecular Genetics of Gliomagenesis

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Formation of low-grade astrocytoma

The p53 gene, a tumor suppressor gene located on chromosome 17p, has an integral role in a number of cellular processes, including cell cycle arrest, response to DNA damage, apoptosis, angiogenesis and differentiation. The p53 gene is involved in the early stages of astrocytoma tumorigenesis 1. p53 mutations and allelic loss of chromosome 17p are observed in approximately one-third of all three grades of adult astrocytomas, suggesting that inactivation of p53 is important in the formation of low grade glioma. Moreover, high-grade astrocytomas with homogeneous p53 mutations evolve clonally from subpopulations of similarly mutated cells present in initially low-grade tumors. The loss of astrocytic p53 function appears to facilitate some events integral to neoplastic transformation, setting the stage for further malignant progression.

Many growth factors and their receptors are overexpressed in astrocytomas, including platelet-derived growth factor (PDGF), fibroblast growth factors (FGFs), and vascular endothelial growth factor (VEGF). PDGF ligands and receptors are expressed approximately equally in all grades of astrocytoma, suggesting that such overexpression is also important in the initial stages of astrocytoma formation. Tumors often overexpress cognate PDGF ligands and receptors in an autocrine stimulatory fashion. Interestingly, loss of chromosome 17p in the region of the p53 gene is closely correlated with PDGF a-receptor overexpression. These observations may imply that p53 mutations have an oncogenic effect only in the presence of PDGF a-receptor overexpression. This interdependence is highlighted by observations that mouse astrocytes without functional p53 become transformed only in the presence of specific growth factors.

Investigations into astrocytoma invasion have highlighted the complex nature of cell-cell and cell-extracellular matrix interactions 8. A variety of cell surface molecules such as CD44 glycoproteins, gangliosides and integrins are differentially expressed in astrocytomas. Some, such as the A2B5 ganglioside, are expressed primarily by non-dividing cells that are migrating; others appear somewhat specific for neoplastic astrocytes. Many of the growth factors expressed in astrocytomas, such as FGF, EGF and VEGF, also stimulate migration 8.

Low grade glioma may also demonstrate LOH on chromosomes 22q and 10q, as well as gain of chromosome 7q and amplification of 8q are frequent.

Progression to anaplastic astrocytoma

The transition from WHO grade II astrocytoma to WHO grade III anaplastic astrocytoma is accompanied histologically by increased cellularity and the presence of mitotic activity, implying that higher proliferative activity is the hallmark of the progression to anaplastic astrocytoma.

Recent studies have suggested that a number of the molecular abnormalities that have been associated with anaplastic astrocytoma converge a one critical cell-cycle regulatory complex which includes the p16, cyclin-dependent kinase 4 (cdk4), cyclin D1 and retinoblastoma (Rb) proteins. The simplest schema suggests that p16 inhibits the cdk4/cyclin D1 complex, preventing cdk4 from phosphorylating pRb, and so ensuring that pRb maintains its brake on the cell cycle 11. Individual components in this pathway are altered in up to 50% of anaplastic astrocytomas and in the majority of GBM.

Chromosome 9p loss occurs in approximately 50% of anaplastic astrocytomas and GBMs, with 9p deletions occurring primarily in the region of the CDKN2/p16 (or MTS1) gene, which encodes the p16 protein 12. The frequency of 9p loss increases not only at the transition from astrocytoma to anaplastic astrocytoma, but also at the transition from anaplastic astrocytoma to GBM. Deletions in primary GBMs almost always involve CDKN2/p16 12,14 and three mutations have been described in primary GBMs with allelic loss of chromosome 9p 15-17. In addition, reduced or absent p16 expression occurs in some malignant gliomas without CDKN2/p16 loss 18, suggesting alternative means, such as hypermethylation, of inactivating this gene in GBMs.

Loss of chromosome 13q occurs in one-third to one-half of high-grade astrocytomas, suggesting the presence of an progression-associated astrocytoma tumor suppressor gene on that chromosome. The 13q14 region containing the RB gene is preferentially targeted by these losses and inactivating mutations of the RB gene occur in primary astrocytomas. Overall, analysis of chromosome 13q loss, RB gene mutations and Rb protein expression suggests that the RB gene is inactivated in about 20% of anaplastic astrocytomas and 35% of GBM. Interestingly, RB and CDKN2/p16 alterations in primary gliomas are inversely correlated, rarely occurring together in the same tumor.

Because amplification of the CDK4 gene and overexpression of cyclin D1 may have similar effects to p16 or pRb inactivation 11, these mechanisms may provide additional alternatives to subvert cell-cycle control and facilitate progression to GBM. CDK4, located on chromosome 12q13-14, is amplified in 15% of malignant gliomas, although this frequency may be higher among cases without CDKN2/p16 loss, perhaps reaching 50% of GBMs without CDKN2/p16 loss 14. In combination, it is likely that up to 50% of anaplastic astrocytomas and perhaps all GBM have alterations in at least one component of this critical cell-cycle regulatory pathway.

Allelic losses on 19q have been observed in up to 40% of anaplastic astrocytomas and GBMs. This tumor suppressor gene may be unique to glial tumors and is involved in all three major types of diffuse cerebral gliomas (astrocytomas, oligodendrogliomas, and oligoastrocytomas). This gene maps to a region of chromosome 19q13.3, telomeric to the marker D19S219 and centromeric to the HRC gene 26,27. A number of candidate genes have been isolated from or mapped to this region, including the BAX gene, whose product negatively regulates apoptosis with bcl-2, but the tumor suppressor gene remains to be identified.

Progression to glioblastoma multiforme

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.

Subsets of glioblastoma multiforme

The assumption that all astrocytomas progress through distinct genetic stages in a linear fashion is most likely an oversimplification. It appears as if there are biologic subsets of astrocytomas which may reflect the clinical heterogeneity observed in these tumors. GBMs can be divided on the basis of molecular genetic analysis. As stated above, loss of chromosome 17p and associated p53 mutation occur in tumors with PDGF-a receptor overexpression, and EGFR gene amplification occurs in tumors with loss of chromosome 10 . However, EGFR gene amplification almost never occurs in GBMs with loss of chromosome 17p: approximately one-third of GBM have p53/chromosome 17p alterations, one third have EGFR gene amplification, and one third have neither change 40. Significantly, those GBMs with loss of chromosome 17p occur in patients younger than those characterized by EGFR gene amplification. In vitro data suggest that primary GBMs with p53 mutations may therefore be expected not to acquire EGFR gene amplification, as activation of the EGF-EGFR system does not produce a growth advantage in such cells.

The genetic pathway involving 17p loss may involve progression from a lower-grade astrocytic lesion, since loss of chromosome 17p, p53 mutation and PDGF-a receptor overexpression occur as commonly in lower-grade astrocytomas as in higher-grade astrocytomas (see above). On the other hand, those GBM with EGFR amplification may arise either de novo or rapidly from a pre-existing tumor, without a clinically-evident, preceding lower-grade astrocytoma. Interestingly, younger age at initial diagnosis has been an important prognostic parameter among patients with GBM, with younger patients faring better than older patients. The predominance of tumors with 17p loss in a younger population of astrocytoma patients may therefore reflect the age-based difference in prognosis. Indeed, in a few studies, patients with p53 mutations had somewhat better prognoses than those without p53 mutations 6,43. In addition, it is possible that those patients with anaplastic gliomas and a previous history of lower-grade glioma that do better clinically ("dedifferentiated GBM") are the same subset as those GBMs with 17p loss. Finally, those GBMs with EGFR gene amplification appear to recur more quickly than those GBM without EGFR gene amplification, further suggesting that tumors with EGFR gene amplification are more rapidly progressing lesions.

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