Proto-oncogenes are the genes which are most frequently found amplified in human
tumor cells. Acquisition of a
drug-resistant phenotype by gene amplification is frequent for in-vitro cultured cells but is very rare in human
tumors. Proto-oncogenes amplified in human
tumors belong essentially to one of three families (erbB, ras, myc) or to the 11q13 locus. Amplification is always specific for the
tumor cells and is not found in constitutional
DNA of the patient, indicating that amplification of the gene is selected for during
tumor growth. For genes of the first three families, amplification results in overexpression in most of the cases. These are strong arguments in favor of a role of this amplification in
tumor progression. The gene whose overexpression is the driving force for the selection of the amplification of the 11q13 locus is not known. The prad1 gene is presently a good candidate. Amplification of one type of proto-oncogene is generally not restricted to one
tumor type. However, the N-myc gene is amplified mainly in
tumors of neuronal or neuroendocrine origin and L-myc amplification is restricted to lung
carcinomas. To understand the role of proto-oncogene amplification and overexpression in
tumor progression it is necessary to know the function of the corresponding
protein in the cell. erbB
proteins are transmembrane receptors for
growth factors. ras genes encode small
GTP-binding proteins which are possibly involved in signal transduction. The myc
proteins are
transcription factors. The expression of the c-myc gene is induced a few hours after cells of various types have been induced to proliferate. The genes of these three families therefore encode
proteins which appear to be involved in signal transduction. It is possible that overexpression of one of them, as a result of gene amplification, makes the cell a better responder to low levels of growth stimuli. For several genes which are found amplified in human
tumors, it was shown that overexpression of the normal
protein could confer a transformed or tumorigenic phenotype to in-vitro cultured cells. In addition, several studies on animal and human
tumor-derived cell lines with an amplified proto-oncogene have established a relationship between proto-oncogene amplification and the tumorigenic phenotype. In
neuroblastomas, it was proposed that down-modulation of MHC
Class I antigens is a consequence of N-myc amplification and that this could be important in the progression toward a metastatic phenotype.(ABSTRACT TRUNCATED AT 400 WORDS)