Somatic Mutations in Normal Tissues: New Perspectives on Early Carcinogenesis

Normal tissues progressively acquire mutations. Some mutations are positively selected, driving clonal expansions that may colonize the majority of a tissue by old age. In several cases mutant clonal expansion is due to biasing stem cell fate toward proliferation. However, the expansionary phase is transient and is followed by reversion toward wild-type behavior so that normal tissue integrity is retained. Here we consider the implications of these findings for carcinogenesis. We propose that to be considered a cancer driver, a mutant gene should be more prevalent in tumors than the normal lineage from which it emerged. Cancer risk is not dependent on mutational burden, but rather may reflect the relative frequency of pro- and anti-oncogenic mutants within a tissue. Understanding the basis of mutant clonal advantage over wild-type cells allows interventions to halt the expansion or even deplete oncogenic mutants from normal tissue, potentially lowering cancer risk. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.