Molecular Genetics of Gliomagenesis: Progression to anaplastic astrocytoma
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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.