Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2021
Erindi/veggspjald / Talk/poster E55
Höfundar / Authors: Sigurgeir Ólafsson (1),Peter J. Campbell (1), Carl A. Anderson (1)
Starfsvettvangur / Affiliations: 1. Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.
Kynnir / Presenter: Sigurgeir Ólafsson
Psoriasis vulgaris is a chronic autoimmune disease of the skin. It is characterized by hyperproliferation of keratinocytes which causes a thickening of the epidermis and extension of epidermal rete into the dermis below. We have used laser capture microscopy to isolate samples of keratinocytes, <0.01mm2 in size, from psoriatic lesions and adjacent non-lesional skin. By whole-exome sequencing of hundreds of microbiopsies from dozens of donors, we compare the psoriatic and healthy epidermis in terms of its clonal structure, mutation burden, mutagen activity and selection landscape. Preliminary results from over 400 exomes indicate that lesional skin is similar to non-lesional skin in terms of mutation burden, clonal structure, mutational signature exposure and proportion of cells that carry putative driver mutations. We observe positive selection of mutations in NOTCH1, FAT1, PPM1D, TP53, ZFP36L2 and NOTCH2 in the skin. In contrast to inflammatory bowel disease, a second chronic inflammatory disease affecting epithelial tissue, we do not observe an enrichment of mutations affecting immune-related genes or pathways. Finally, we describe the mutational consequences of phototreatment with psoralens. This cytotoxic treatment leaves a characteristic mutational signature with a large transcriptional strand bias. In one patient, PUVA treatment had resulted in hundreds of thousands of mutations and enabled the expansion of heavily mutated clones in the skin.