Figure ll reveals the mutation frequency at the locus for adenine phosphoribosyltransferase in mammalian cells. As with the complementation analysis, these data reveal that the spectrum of mutations differs, depending on the nature of the mutagen. This observation is not surprising, given the different mutations arising from different mutagens. An understanding of mutagenesis is essential to understanding carcinogenesis, since essentially all carcinogens are mutagens. Carcinogenesis is a multistage process resulting from carcinogen-induced genetic and epigenetic alterations.
Initiation is thought to result from carcinogen-induced DNA damage.
Promotion may be defined as the clonal expansion of the initiated cells through a series of genetic and epigenetic changes that produce various biochemical changes in the cells. The decreased responsiveness to signals adverse to cell proliferation is thought to underlie the clonal expansion of initiated cells. Protooncogenes are normal cellular genes that are involved in the control of growth and differentiation. Carcinogens can activate cellular protooncogenes to oncogenes by base substitutions, chromosomal translocations, and gene amplification. Alternatively, RNA viruses can introduce mutated forms of these genes into infected cells or activate dormant cellular genes by the integration of viral transcriptional regulatory sequences at the promoter region of the protooncogene.