Abstract 2857: Analysis of epidermal mutation burden across diverse skin tones

Abstract Objectives/Goals: Despite the documented link between UV exposure and skin cancer, the role of pigmentation in preventing skin carcinogenesis is not fully understood. 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 diverse skin tones, which will uncover potential differences in susceptibility and mutation patterns. Methods/Study Population: We collected skin biopsies from various body sites exposed to different levels of habitual sun exposure. Next, we cultured individual skin cells, including keratinocytes, melanocytes, and dermal fibroblasts, ex vivo to form small colonies of daughter cells. We extracted DNA and RNA from these colonies and amplified the nucleic acids in vitro. Subsequently, we sequenced the expanded clones at exome-level resolution. For our study, we collected samples from seven dark skin donors ranging in age from 35 to 83 years. For comparison, we also analyzed mutations in skin cells from 33 donors with light skin tones, who served as the control group. Results: Our preliminary analysis of the existing data suggests expected trends. The average mutation burden in individuals with light skin tones was 4.967 Mut/Mb, whereas in those with dark skin tones, it was only 1.609 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. There is evidence to suggest that individuals with darker skin may have fewer cumulative mutations, possibly decreasing their risk of skin cancer. One limitation of our study is that we are underpowered to draw definitive conclusions, as we had to group specific anatomical sites and lacked data from all skin cell lineages across all sites. Despite this, our results revealed variations in mutational burdens between different anatomical locations, with higher burdens observed in areas subjected to greater UV exposure. These findings suggest a potential link between UV exposure and mutational load. To build on our current findings, we plan to increase the sample size and refine our control over site and cell lineage factors to enhance the strength of our results. Conclusion/Implications: Understanding how skin tone affects the risk of skin cancer is imperative for gaining a deeper insight into the mechanisms driving cancer development across diverse populations. While individuals with darker skin tones are less commonly diagnosed with skin cancer, they often experience more advanced stages at diagnosis due to delayed recognition of symptoms. By understanding the differences in mutational patterns and the role of UV exposure in darker skin, we can improve early detection and treatment strategies for this underserved group and refine screening and prevention methods for lighter-skinned individuals who are at higher risk. Citation Format: Rojina Nekoonam, Aravind K. Bandari, Delahny Deivendran, Bishal Tandukar, Harsh Sharma, Alan H. Shain. Analysis of epidermal mutation burden across diverse skin tones [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2857.