Tumour promotion through the lens of evolution

Almost all tumours carry one or more cancer driver mutations, which are essential for cell transformation. However, recent advances in cancer genomics have demonstrated that normal human tissues contain millions of cells carrying known driver mutations, while preserving homeostasis. Most of these mutated cells will never transform into tumours. Moreover, studies of known or suspected human carcinogens have shown that the majority are not mutagens. These observations suggest that exogenous carcinogenic exposures might increase cancer risk by modifying selective constraints, promoting the expansion of pre-existing clones carrying specific oncogenic mutations. In this Review, we propose a synthesis between ideas put forward almost a century ago based on seminal experiments on carcinogen-induced tumours in mice, observations made by cancer epidemiologists over several decades, and the recent revelation that normal human tissues are a patchwork of mutant clones. The repeated interplay between variation and selection-the first principles of Darwinian evolution-underlies the clonal selection leading to tumorigenesis. A deeper understanding of these processes can enhance prospects for cancer prevention by eliminating or mitigating the effects of environmental or endogenous tumour promoters.