Cutaneous squamous cell carcinomas (cSCC) evolve from early mutated clones of keratinocytes. Numerous genomic regions are highly susceptible to UV mutagenesis. Previous studies indicate differences in clonal mutation burden across skin sites of differing UV exposure. Our current work is aimed at identifying mutations in normal skin (NS) that are associated with more advanced photocarcinogenesis (PCG). We have used our computational tool “hotSPOT” to identify regions most likely to be mutated in cSCC, actinic keratoses (AK), and sun-exposed (SE) NS. The genomic locations of mutation hotspots in cSCC and NS were compared, revealing significant overlap (mean = 28.21%, p < 0.05). Based on this finding, we hypothesized that mutational hotspots found in both cSCC and NS may aid in evaluating the photocarcinogenic progression of SE NS. cSCC mutational hotspots were then evaluated in NS. Numerous areas of known cancer-promoting genes were enriched with mutations in NS. Further analysis revealed cSCC mutation hotspots capture more mutations in chronically SE NS than intermittently SE NS (p < 0.0001). We then used logistic regression to differentiate NS samples by SE history based on mutation frequency in cSCC, AK, and NS hotspots, which yielded an overall classification accuracy of 81.5%. Subset selection of these data identified genomic regions of mutation hotspots shared by NS and cSCC were most influential for identifying sun-exposure status. Our results show that hotspots shared by NS and cSCC can serve as targets for genomic studies of early PCG. Many highly mutated regions in cSCC have not been studied in NS. Therefore, our data highlight the need for a comprehensive assessment of all cSCC mutation hotspots in SE NS samples to identify all high-yield genomic areas for studying early PCG.
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