Prognostic Relevance of Transforming Genes

Abstract

Malignant transformation is considered the result of a multipstep process in which cells aquire mutations of genes that are critical for the regulation of cell proliferation and differentiation (Bishop 1987; Weinberg 1989). In astrocytic gliomas several different mutations have been identified, some of which are confined to certain grades of malignancy (Collins 1990). Amplification and overexpression of the gene encoding the epidermal growth factor receptor (EGFR) is nearly exclusively present in glioblastomas (Libermann 1985; Ekstrand 1991; Agosti 1992). Amplification of EGFR gene fragments with large deletions encoding a truncated receptor has been described as well as amplification of the intact gene encoding a functional receptor (Yamazaki 1988; Humphrey 1990,1991; Ekstrand 1992). An amplified and overexpressed EGFR may or may not be capable of being activated by its main ligand transforming growth factor-α (TGF-α; Yamazaki 1988; Humphrey 1991). In many astrocytic gliomas TGF-α itself has been found to be overexpressed in a large number of these tumors without evidence of genetic alteration (Schlegel 1990; Ekstrand 1991), and an autocrine mechanism of growth stimulation by the EGFR/TGF-α system has been postulated in glioma cells (Ekstrand 1991). Mutations and allelic loss of the tumor suppressor gene p53 have been reported in astrocytic gliomas (Nigro 1989; v. Deimling 1992; Frankel 1992; Fults 1992). It has been reported that in low-grade astrocytomas cells with mutations of the p53 gene represent a minority. The fact that these cells may undergo clonal expansion in recurrent malignant gliomas suggests that p53 mutations play a significant role in malignant progression (Sidransky 1992).