Somatic Mutations in Normal Tissues: New Perspectives on Early Carcinogenesis

Abstract

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.

Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations

“…Considering our data, it is reasonable to speculate that, well before tumor onset, the expansion of ARID1A mutant clones might be restrained by the activity of the immune system and/or by a reduced fitness compared with neighboring normal cells. Cancer driver mutations in nontumoral tissues are often associated with inflammatory disorders ( 50 , 51 ). The selective pressure imposed by the environment might gradually favor the acquisition of mutations able to bypass immunosurveillance and provide growth advantages, especially in the context of chronic inflammation.…”