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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: Protocol no.: 518-2/19-12-2019.