KIT Mutations Are More Common in Mucosal than Acral Melanoma: A Case-Series of 152 Patients from a Single Centre

Background/Objectives: Acral (AM) and mucosal melanomas (MM) have certain genetic similarities compared to non-acral cutaneous melanomas and share a restricted influence of UV radiation in their etiology. Yet, AM and MM arise in quite different locations from a histological perspective. This study aimed to report differences between AM and MM for the most prominently mutated genes in melanoma: BRAF, NRAS, KIT, and TERT promoter. Methods: We conducted a retrospective, single-center study including 152 patients diagnosed with AM (n = 121) or MM (n = 31) at the Fundación Instituto Valenciano de Oncología between 2000 and 2024. Clinical and histopathological data were collected, and mutational analyses of BRAF, NRAS, KIT, and the TERT promoter were performed using targeted sequencing. Results: MM presented with significantly greater Breslow thickness and higher rates of hematogenous metastasis compared to AM. While BRAF, NRAS, and TERT promoter mutations were similarly distributed between subtypes, KIT mutations were significantly more frequent in MM (33% vs. 12.3%; p = 0.043) and exhibited a broader mutational spectrum. Survival outcomes were poorer in MM, with lower 5- and 10-year survival rates compared to AM. Discussion: Despite shared UV-independent biology, AM and MM differ in clinically and molecularly meaningful ways. The higher prevalence and diversity of KIT mutations in MM suggest subtype-specific oncogenic mechanisms and potential therapeutic implications. These findings support a more refined classification of UV-independent melanomas based on anatomical and molecular distinctions.