Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin

Abstract

AbstractSomatic mutations are hypothesised to play a role in many non-neoplastic diseases. These diseases may also shape the somatic mutation landscape of affected tissues after onset. We performed whole-exome sequencing of 1182 microbiopsies dissected from lesional and non-lesional epidermis from 111 patients with psoriasis, a chronic inflammatory disease of the skin, to search for evidence that somatic mutations in keratinocytes may influence the disease process and to characterise the effects of the disease on the mutation landscape of the epidermis. We show that psoriasis is associated with increased mutation burden of the cell-intrinsic signatures SBS1 and SBS5 but not of UV-light, which remains the dominant mutagen in psoriatic skin. Despite the hyperproliferation of keratinocytes that characterises psoriasis, lesional skin remains highly polyclonal, showing no evidence of spread of clones carrying potentially pathogenic mutations. We find that the selection forces operating in the epidermis remain mostly unchanged in psoriasis and the mutational landscape continues to be dominated by clones carrying mutations in genes recurrently mutated in normal squamous epithelia. There is evidence of positive selection in previously reported driver genes, NOTCH1, NOTCH2, TP53, FAT1 and PPM1D and we also identify four driver genes (GXYLT1, CHEK2, ZFP36L2 and EEF1A1), that have not been previously described in studies of normal skin but which we hypothesise are selected for in squamous epithelium irrespective of disease status. We describe the mutagenic effects of psoralens, a class of chemicals previously found in some sunscreens and which remain a part of a common photochemotherapy treatment for psoriasis (psoralens and UV-A, PUVA). Psoralens leave a distinct mutational signature in the genomes of exposed cells that is tightly linked with transcription, showing evidence of both transcription-coupled repair and transcription-coupled damage. These results suggest that somatic mutations in keratinocytes are unlikely to influence the pathogenesis of psoriasis and that while psoriasis has only modest effect on the mutation landscape of the skin, PUVA treatment has the potential to exert a unique and larger effects.