Carcinogenesis: Mutations and Mutagens

In normal human cells there is a steady accumulation of mutations with time. We argue that the great majority of these mutations arise spontaneously and are due to endogenous factors or processes that damage DNA. A small fraction of these mutations converts a normal cell into a cell that is initiated towards the development of cancer. We propose that, in general, these initiated cells are more susceptible to the mutagenic effects of exogenous carcinogenic agents than to the mutagenic effects of endogenous factors. Indeed, it can be assumed that in most instances the initiation event is due to a mutation which causes inactivation or loss of a mutation avoidance gene, such as the p53 gene, or a gene which is involved in the repair of damaged DNA. Recent studies have shown that most of such mutations lead to a considerable enhancement in the mutagenicity of many exogenous agents, whereas the mutagenicity of endogenous factors is less affected. Furthermore, the progressive accumulation of mutations with increasing age implies that more initiated cells are likely to be found in older individuals. Therefore, sensitivity to the carcinogenic effect of exogenous mutagens can generally be assumed to increase in older people.