Molecular Genetics of Gliomagenesis: Formation of low-grade astrocytoma

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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.

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