Mutational approaches to the study of carcinogenesis.

A number of circumstantial lines of evidence are consistent with the somatic mutation theory of carcinogenesis, but there has been a paucity of experimental data that either support or contradict the genetic theory. In this paper, we summarize the predictions, the recent experimental approaches, and the problems involved in testing the theory. Results are presented that define the conditions and demonstrate the existence of two-stage processes of mutagenesis and carcinogenesis in vitro. We conclude that mutagenesis is responsible for the initiation of carcinogenesis and an epigenetic mechanism is responsible for its promotion. Carcinogenic agents can induce a stable transformation of a cell by either mutation or epigenetic alteration in gene expression. This conclusion has led us to propose a new integrative theory of carcinogenesis, encompassing the tenets of four main theories: (1) the mutation and epigenetic basis for carcinogenesis, (2) the two-stage theory of carcinogenesis, (3) a general theory of carcinogenesis, and (4) the somatic deletion mutation theory of carcinogenesis.