Abstract Introduction and aims Ultraviolet (UV) radiation is the major environmental cause of skin cancer, yet ultraviolet (UV)-driven systemic protein responses remain poorly defined. We aimed to: (i) derive an ambient UV plasma proteomic signature in UK Biobank; (ii) validate it in an independent human solar-simulator intervention cohort; and (iii) test how strongly this UV-driven signature aligns with proteomic profiles of incident basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous melanoma in UK Biobank. Methods In 50 000 UK Biobank participants we linked residential addresses to a satellite-based model to estimate ambient UV dose and combined this with a plasma proteomics panel (∼2000 proteins), deriving a UV proteomic signature. This signature was further validated in an independent solar-simulator intervention cohort of healthy volunteers (n = 10), using within-person paired pre-/post-UV profiling on the same panel; Using UK Biobank cancer registration, we generated plasma proteomic signatures for incident BCC, SCC and melanoma, and quantified their similarity to the UV signatures using Fisher’s exact tests and Jaccard indices. Results The UV signature was dominated by downregulated proteins enriched for extracellular matrix, vascular and immune pathways, with a smaller set of increased skin-related markers (e.g. KRT5). In the solar-simulator cohort, UV-response proteomic changes were consistent and strongly correlated with the UK Biobank UV signature, supporting a robust UV-driven programme across independent cohorts. When compared with skin cancer signatures, the UV-driven programme aligned most strongly with BCC, showed weaker similarity with SCC, and did not align with melanoma. Conclusions We establish a reproducible human plasma UV proteomic signature supported by both UK Biobank and a controlled solar-simulator intervention and show that this UV-driven programme selectively maps onto the proteomic signature of BCC and SCC risk rather than melanoma. These findings nominate a circulating, UV-responsive protein panel that could be developed into a UV exposure biomarker score to improve skin cancer risk stratification.
Gu et al. (Tue,) studied this question.
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