MC1R and IRF4 Gene Variants Are Associated with p16INK4a-Positive Epidermal Cells

Basal cell carcinoma (BCC) cases in sun-protected skin are estimated to be between 20 and 33% of total cases, highlighting a non-UVR influence on BCC incidence. In this study, we tested the hypothesis that BCC risk is associated with cell senescence in sun-protected skin by comparing senescence marker p16INK4a cell counts in skin biopsies from participants of the Leiden Longevity Study with a BCC genetic risk score, calculated from single nucleotide variation (SNV) data from the same participants (n = 166). We found an association (P < .05) between p16INK4a-positive cells in the epidermis and the BCC genetic risk score but not among those in the dermis, which was driven by SNVs in the MC1R (P < .001) and IRF4 (P = .02) genes. Because melanocytes are the dominant p16INK4a-positive cell in sun-protected epidermal skin, these findings suggest that p16INK4a-positive melanocytes could be contributing to BCC risk. However, an indirect association between p16INK4a-positive cells and BCC risk through SNV pleiotropy is alternatively possible, and confirmation of how many p16INK4a epidermal cells are truly senescent is required. Because MC1R and IRF4 genetic variants are strongly linked to skin cancer risk, further investigation into a potential role for these p16INK4a-positive cells in skin cancer risk is warranted.