385 Impact of skin pigmentation on genomic alterations and mutation load

Objectives/Goals: Despite the documented link between ultraviolet (UV) exposure and skin cancer, the potential protective role of pigmentation in preventing skin carcinogenesis is not fully understood. This project will test the hypothesis that individuals with light skin tones are more susceptible to skin cancer due to a higher accumulation of somatic mutations from UV exposure. Methods/Study Population: Skin biopsies were collected from various anatomical sites of seven donors aged 70 to 80 years with dark skin tones and used to generate clones of normal skin cells. The clones were then subjected to whole-exome and RNA sequencing. We developed a workflow that allows us to accurately detect somatic mutations in clonal expansions of individual cells with high specificity and sensitivity. For comparison, we also analyzed mutations in skin cells obtained from individuals with light skin tones, who served as our control group. In the future, we plan to employ admixture analysis to clarify the impact of race on somatic mutations by examining ancestral genetic contributions. Results/Anticipated Results: Our preliminary analysis of the existing data supports our hypothesis. The average mutation burden in individuals with light skin tone was found to be 3.778 Mut/Mb, whereas in those with dark skin tones, was only 0.818 Mut/Mb. These findings align with the prevailing hypothesis that melanin acts as a protective factor against skin cancer, as it appears to reduce the mutagenic effects of UV radiation. This suggests that individuals with darker skin may have a lower cumulative mutational load, potentially contributing to their reduced risk of developing skin cancers such as melanoma. Similarly, our results showed variations in mutational burdens across different anatomical sites, which seemed to be influenced by differing levels of UV exposure, with the highest burdens observed in areas with the greatest exposure. Discussion/Significance of Impact: Understanding how skin cancer operates in darker-skinned individuals is imperative for tailoring effective screening and targeted therapies to meet their specific needs. In the long run, elucidating the mechanisms underlying skin cancer development in this demographic will help refine screening protocols and prevention recommendations.