Selection of oncogenic mutant clones in normal human skin varies with body site.

Abstract

Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high and low risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet (UV) light, but mutational signature analysis suggested differences in DNA repair processes between sites. 11 mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine scale mapping revealed 10% of clones had copy number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is dense patchwork of mutant clones arising from competitive selection that varies by location.