Melanocortin-1 receptor variants and telomerase reverse transcriptase promoter mutations as prognostic biomarkers in stage IIB–IIC melanoma

Stage IIB-IIC cutaneous melanomas carry a substantial risk of recurrence and disease-related mortality despite complete surgical excision, highlighting the need for reliable prognostic biomarkers. We retrospectively analyzed 153 patients with stage IIB-IIC cutaneous melanoma who underwent surgery at the Instituto Valenciano de Oncología between May 2000 and August 2024. Recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS) were estimated using Kaplan-Meier methods. Associations between clinicopathologic and molecular characteristics and survival outcomes were assessed by log-rank test and Cox proportional hazards models. At a median follow-up of 81.6 months, median RFS, DFS, and OS were 43, 31, and 50 months, respectively. In univariate analyses, both telomerase reverse transcriptase (TERT) promoter mutations [hazard ratio = 0.38, 95% confidence interval (CI) = 0.18-0.8, P = 0.008] and the absence of melanocortin-1 receptor (MC1R) variants (hazard ratio = 0.38, 95% CI = 0.16-0.91, P = 0.024) were significantly associated with RFS. In multivariate analyses, only TERT promoter mutations remained an independent predictor of both RFS (hazard ratio = 0.44, 95% CI = 0.20-0.96, P = 0.038) and DFS (hazard ratio = 0.47, 95% CI = 0.24-0.93, P = 0.030). Patients harboring TERT promoter mutations exhibited significantly poorer survival outcomes compared with those with wild-type TERT promoter status. Combined analysis supported the contrasting prognostic roles of TERT and MC1R. Our findings identify TERT promoter mutations as an independent prognostic factor and suggest a potential protective role of MC1R variants in stage IIB-IIC cutaneous melanoma.