Cancer is driven by genomic mutations in ‘cancer driver’ genes, which have essential roles in tumor development. These mutations may be caused by exposure to mutagens in the environment or by endogenous DNA-replication errors in tissue stem cells. Recent observations of abundant mutations, including cancer driver mutations, in histologically normal human tissues suggest that mutations alone are not sufficient for tumor development, thus prompting the question of how single mutant cells give rise to neoplasia. In a concept supported by decades-old data from mouse tumor models, non-mutagenic tumor-promoting agents have been posited to activate the proliferation of dormant mutated cells, thus generating actively growing lesions, with the promotion stage as the rate-limiting step in tumor formation. Non-mutagenic promoting agents, either endogenous or environmental, may therefore have a more important role in human cancer etiology than previously thought.
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This work was supported by a Cancer Research UK Grand Challenge Award (C98/A24032), US National Cancer Institute (NCI) grants R35CA210018 and UO1CA176287, and the Barbara Bass Bakar Professorship of Cancer Genetics (to A.B.). The author thanks numerous colleagues for discussions.
A.B. is a member of the Scientific Advisory Board of Mission Bio, Inc. and has received funding support from Novartis and Bristol Myers Squibb.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Balmain, A. The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk. Nat Genet 52, 1139–1143 (2020). https://doi.org/10.1038/s41588-020-00727-5