Genetic Markers of Tumor Multiplicity in Non-melanoma Skin Cancer: Associations of 19 SNPs in an Italian Cohort

Ultraviolet exposure is the main environmental risk factor for non-melanoma skin cancers (NMSCs), but genetic susceptibility also contributes to variability in disease burden among individuals. This study analyzed selected single-nucleotide polymorphisms (SNPs) in genes related to vitamin D and nicotinamide adenine dinucleotide metabolism, DNA repair, inflammation, and pigmentation as potential biomarkers for NMSC risk in an Italian cohort. Participants were stratified into low- and high-risk groups on the basis of tumor burden. No significant differences were observed in demographic or phenotypic factors between the groups; however, chronic sun exposure was associated with an increased risk. A total of 19 SNPs showed significant associations with NMSC multiplicity. Most of these SNPs were noncoding variants that likely influence gene expression or transcript stability. Specific variants in the NNMT, NFKBIA, ERCC6, XPA, LIG1, LIG3, and ZNF365 genes were more prevalent in individuals at high risk. Literature-based functional data indicate that the identified NFKBIA and ERCC6 SNPs are particularly relevant to NMSC risk, as NFKBIA variants may promote inflammation, and the ERCC6 variant can impair DNA repair. These results underscore the significance of regulatory genetic variation in NMSC susceptibility. The identified SNPs could represent useful biomarkers for genetic risk stratification and support the development of personalized prevention strategies based on genetic profiles. Protocol no.: 518-2/19-12-2019. Non-melanoma skin cancers are very common tumors. Although sun exposure is the main cause, not everyone who receives similar amounts of sunlight develops the same number of tumors. This suggests that individual genetic differences may also influence tumor risk. This study examined whether small differences in DNA can explain why some people develop multiple non-melanoma skin cancers. These differences, known as “genetic variants,” are a normal part of human biology and can influence how the body responds to sun damage. We examined genetic variants in some genes responsible for metabolism, inflammation, DNA repair, and skin pigmentation in a group of Italian patients. We compared individuals with a low number of skin tumors with those with many tumors. The two groups were similar in terms of age, sex, and skin type. However, those with long-term sun exposure had more tumors. We identified 19 genetic variants that were more prevalent among individuals with multiple skin cancers. Most of these variants were found in regions of DNA that control how genes are activated, rather than in regions that alter the structure of proteins. Some of these genetic variants were associated with increased inflammation or reduced ability to repair DNA damage in response to sunlight. Both processes can increase the risk of developing skin cancer. Overall, these results suggest that genetic differences, together with sun exposure, help to explain why some individuals are more prone to developing multiple non-melanoma skin cancers. This information may support more personalized prevention strategies in the future.