RELATIONSHIP BETWEEN MUTAGENESIS AND CARCINOGENESIS*

Abstract— Since the neoplastic condition is a phenotypic expression of the genome of the tumor cells, it is reasonable to assume that the neoplastic state can be the result of the alteration of gene activity by either mutagenesis or gene modulation. The review of the literature seems to support the hypothesis that both mutations and epigenetic processes are components to carcinogenesis. Consistent with the mutation theory of cancer are: (1) the clonal nature of tumors; (2) the mutagenicity of most (but not all) carcinogens; (3) correlation of high mutation frequencies in cells of cancer‐prone human fibro‐ blasts lacking DNA repair enzymes; (4) correlation of in vitro DNA damage, in vitro mutation and transformation frequencies with in vivo tumorigenesis; (5) age‐related incidences of various hereditary tumors; and (6) the correlation between photoreactivation of DNA damage and the biological amelioration of UV‐induced neoplasms. Supporting the epigenetic theory of carcinogenesis is the reversion of certain types of neoplastic cells to a state allowing normal development. These latter studies demonstrate the totipotency of the genes in some types of malignant cells. An integrative theory of carcinogenesis is presented that synthesizes the mutation and epigenetic theories with Comings' general theory of carcinogenesis and the 2‐stage theory of carcinogenesis. Data are presented that test the predictions of the 2‐stage theory of carcinogenesis, and that support the hypothesis that mutagenesis plays a major role in carcinogenesis (initiation phase) and that gene modulation of repressed mutations is responsible for tumor promotion.