Genomic analysis of UV-induced mutations in normal skin cells of dark and light-skinned individuals

Summary: Abstract Body: This project aims to investigate how pigmentation influences the earliest stages of skin cancer development by examining the genomic landscape in skin cells across individuals of light and dark skin tones. We obtained punch biopsies from body sites with varying sun exposure. Somatic mutations in melanocytes and keratinocytes were identified through a multi-step process: single cells were expanded into small colonies, their genetic material was extracted and amplified, and the resulting nucleic acids were sequenced at the exome level. In total, we sequenced 67 melanocytes and 25 keratinocytes from 3 African American donors. For comparison, we also analyzed mutations in 237 melanocytes and 131 keratinocytes from 14 white donors. The mutation burdens were, on average, approximately twice as high in melanocytes from white donors after accounting for cell type and anatomic site. These findings suggest melanin may mitigate the effects of UV-induced mutations. We also observed a higher frequency of cytosine-to-thymidine transitions at dipyrimidine sites in skin cells from individuals with lighter skin tones compared to those with darker skin. These mutations are markers of UV radiation-induced DNA damage. Furthermore, we analyzed mutational differences across chronically, intermittently, and minimally sun-exposed regions between the two groups to assess the impact of UV exposure on mutation rates. Our analysis revealed that regions with intermittent sun exposure (i.e., shoulder) exhibit higher levels of DNA damage compared to chronically exposed areas, such as the face. This suggests that DNA repair mechanisms may vary across different anatomical sites. These findings could improve our understanding of skin cancers in all populations, particularly in areas of the body less exposed to the sun or in individuals with lower cumulative UV exposure. Moving forward, we strive to refine early detection methods and create personalized screening guidelines that address the diverse factors contributing to skin cancer risk. Rojina Nekoonam¹, Aravind K. Bandari¹, Bishal Tandukar¹, Delahny Deivendran¹, Harsh Sharma¹, Alan H. Shain¹ 1. Dermatology, University of California San Francisco, San Francisco, CA, United States. UV Biology/Injury and Non-melanoma Cancers