The Effect of Photoaging on the Accumulation of Somatic Mutations in Cancer-Free Human Skin

Sunlight is the principal aetiological factor associated with skin cancer development. However, genetic and phenotypic factors also contribute to skin cancer risk. In this study, we deeply sequenced 46 cancer genes in normal skin biopsies from 127 healthy donors. Our results reveal an exponential accumulation of UV-related somatic mutations with age, matching skin cancer incidence. The increase of mutational burden is in turn modified by an individual’s skin phototype. Somatic mutations preferentially accumulated in cSCC driver genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our findings reveal that aged, sun-exposed normal skin is an extended mosaic of multiple clones with driver mutations, poised for the acquisition of transforming events.