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

Somatic 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. ### Competing Interest Statement S.W. is co-principal investigator of the German Atopic Eczema Registry TREATgermany; has received institutional research grants from Sanofi Deutschland GmbH, LEO Pharma, and La Roche Posay; has performed consultancies for Sanofi-Genzyme, Regeneron, LEO Pharma, AbbVie, Pfizer, Eli Lilly, Kymab, and Novartis; has lectured at educational events sponsored by Sanofi-Genzyme, Regeneron, LEO Pharma, AbbVie, Novartis, and Galderma; and is involved in performing clinical trials with many pharmaceutical companies that manufacture drugs used for the treatment of psoriasis and atopic eczema. C.A.A. has received consultancy or lecture fees from Genomics plc, BridgeBio and GlaxoSmithKline. ### Funding Statement This research was funded in part by the Wellcome Trust [Grant numbers 206194 and 108413/A/15/D]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All donors gave informed consent for genetic research of the material and the study was approved by the research ethics committee of Christian-Albrechts University in Kiel (A100/12), the National Health Service (NHS) Research Ethics Committee (Yorkshire & The Humber - South Yorkshire Research Ethics Committee, REC ID 20/YH/0244, IRAS ID 286843) and by the Wellcome Trust Sanger Institute Human Materials and Data Management Committee (approval number 20/0085). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Raw sequencing data are available in the European Genome-phenome Archive (EGA) under accession number EGAS00001004882. Intermediary and supporting files, including mutation calls, mutational cluster assignments, phylogenetic trees, histological images, spatial relationship matrices and more are available in a Mendeley data repository (DOI:10.17632/rfcy88sb9s.1). Code supporting the main analyses of the manuscript is provided in supplementary files. Custom scripts documenting the mutation filtering and clustering, signature extraction and more are publicly available at https://github.com/Solafsson/somaticPsoriasis DOI:10.17632/rfcy88sb9s.1