Genetic diversity in melanomagenesis: a comprehensive analysis of BRAF, NRAS, KIT and novel mutations across melanoma subtypes

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BACKGROUND AND AIM: Melanomagenesis involves genetic alterations affecting multiple oncogenic pathways, with BRAF and NRAS mutations representing frequently studied drivers. Recent evidence suggests melanoma development encompasses a broader spectrum including KIT mutations and novel variants exhibiting population-specific patterns. This study aimed to characterize the genetic landscape of melanomagenesis by analyzing BRAF, NRAS, KIT and novel mutations across melanoma subtypes in a Turkish cohort. METHODS: Sixty-six genetic materials from 55 melanoma patients (2000-2016) were analyzed using targeted next-generation sequencing of 17 melanoma-relevant genes. Mutation profiling characterized genetic diversity across histological subtypes, with associations between molecular alterations and clinicopathological parameters evaluated using Fisher's exact test and Kruskal-Wallis test. RESULTS: Significant genetic diversity was observed, with 60% of cases harboring mutations. Analysis identified 22 wild-type cases, 13 BRAF mutations (23.6%), 4 NRAS mutations (7.3%), 6 KIT mutations (10.9%), and various alterations in TP53, KNSTRN, KRAS, PIK3CA, CDKN2A, OXA1L, and RAC1. Multiple concurrent mutations occurred in 5 cases (9.1%). Notably, BRAF mutation patterns differed substantially from Western populations: complete absence in superficial spreading melanomas (0.0% versus 50-70% in Caucasian cohorts) with enrichment in nodular melanomas (36.4%). KIT mutations showed significant enrichment in mucosal melanomas (33.3%, P = 0.003). A novel OXA1L frameshift mutation (p.A54Sfs*100) was identified. CONCLUSION: Melanomagenesis in the Turkish population demonstrates substantial genetic diversity with population-specific mutation patterns that diverge from Western paradigms. The absence of BRAF mutations in superficial spreading melanomas suggests distinct genetic pathways potentially related to different UV exposure patterns, genetic susceptibility, or gene-environment interactions. These findings have important implications for precision medicine, as therapeutic strategies developed in Western populations may require adaptation for diverse ethnic groups. Comprehensive genomic profiling including NF1 in larger multi-institutional cohorts is needed to fully characterize population-specific melanomagenesis mechanisms.

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