Knowledge Bank

Melanoma is the malignant transformation of pigment-producing skin cells called melanocytes. The Centers for Disease Control (CDC) state that melanoma is responsible for 7.4% of cancer deaths and is the deadliest form of skin cancer. Prior work from our lab has shown that a single ultraviolet (UV) exposure accelerates tumor formation and increases the mutational burden of melanomas in Genetically Engineered Mouse Models (GEMMs) that are pigmented. However, higher melanoma risk is associated with albinism, which may be due to the protective role that melanin plays in guarding against UV radiation. Here, I used GEMMs which express one of the most frequent genetic drivers of human melanoma, oncogenic NRAS, to study the role of skin pigmentation in melanoma initiation and progression. Our GEMMs were initially designed on a pigmented, C57Bl/6 background and an albino (Tyr c) allele was introduced to our existing GEMMs through genetic backcrosses, creating NRAS-mutant melanoma models that were either black or albino. The mice were exposed to UV and monitored for spontaneous melanoma formation. Tumor DNA and RNA were analyzed for signatures of UV-induced damage using both whole exome and RNA sequencing. From this experiment, we saw no significant difference in tumor formation or growth between the two groups. Additionally, the frequency of single nucleotide variants and indels was not significantly different between tumors from the albino and black groups. However, an enrichment of T→ G mutations was found in the albino tumor samples. From this we concluded that the presence of melanin does not slow or protect against the initiation and growth of melanoma in these mice. These results challenge the idea that melanin provides the most significant protective advantage against melanoma formation and suggests that there may be other genetic factors responsible for the difference in melanoma incidence among albino and pigmented populations. Additional experiments will provide a better understanding of how UV carcinogenesis differs in populations at highest risk for melanoma, which could lead to new preventative methods.