Molecular Genetics of Gliomagenesis: Subsets of glioblastoma multiforme

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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 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.
  

Latest revision as of 18:32, 10 July 2008

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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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