Differential STING and p53 expression in epidermodysplasia verruciformis-associated versus non-EV cutaneous squamous cell carcinomas

Abstract Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent cutaneous β-human papillomavirus infection and increased risk of cutaneous squamous cell carcinoma (cSCC). The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway links cytosolic DNA sensing, genomic instability and innate immune activation, but its expression in EV-associated cSCC remains poorly defined. We quantified STING, p53 and BCL2 immunohistochemical expression in tissue microarrays containing 47 EV-associated and 83 non-EV cSCCs. Tumor H-scores were medians across valid cores; primary comparisons used patient-clustered generalized estimating equations (GEE). STING expression was higher in EV-associated tumors (median H-score 192.4 vs. 149.5); in grade-adjusted GEE, EV status was associated with a + 37.2-unit difference (95% confidence interval [CI] 23.4–51.0; p < 0.001). The EV–non-EV STING difference varied by histological grade (interaction p = 0.0067), with the largest estimated difference in grade 1 tumors. p53 expression was also higher in EV tumors (97.7 vs. 36.3; adjusted difference + 43.8, 95% CI 18.8–68.8; p < 0.001), and EV tumors had higher odds of belonging to a higher p53 tertile (odds ratio [OR] 3.54, 95% CI 1.98–6.32; p < 0.001). BCL2 remained low and was not significantly associated with EV (adjusted difference − 1.93, 95% CI − 4.84 to 0.98; p = 0.193). STING and p53 remained positively associated after adjustment for histological grade, EV status and patient clustering. These findings define an altered STING protein-expression phenotype in EV-associated cSCC, accompanied by increased p53 expression but no independent BCL2 association, and support functional investigation of cGAS–STING signaling.