Efficiency of carcinogenesis: Is the mutator phenotype inevitable?

Cancer development requires multiple oncogenic mutations. Pathogenic mechanisms which accelerate this process may be favored carcinogenic pathways. Mutator mutations are mutations in genetic stability genes, and increase the mutation rate, speeding up the accumulation of oncogenic mutations. The mutator hypothesis states that mutator mutations play a critical role in carcinogenesis. Alternatively, tumors might arise by mutations occurring at the normal rate followed by selection and expansion of various premalignant lineages on the path to cancer. This alternative pathway is a significant argument against the mutator hypothesis. Mutator mutations may also lead to accumulation of deleterious mutations, which could lead to extinction of premalignant lineages before they become cancerous, another argument against the mutator hypothesis. Finally, the need for acquisition of a mutator mutation imposes an additional step on the carcinogenic process. Accordingly, the mutator hypothesis has been a seminal but controversial idea for several decades despite considerable experimental and theoretical work. To resolve this debate, the concept of efficiency has been introduced as a metric for comparing carcinogenic mechanisms, and a new theoretical approach of focused quantitative modeling has been applied. The results demonstrate that, given what is already known, the predominance of mutator mechanisms is likely inevitable, as they overwhelm less efficient non-mutator pathways to cancer.