NRAS Mutations in Different Melanoma Histotypes: Molecular and Clinical Implications

Abstract Purpose of Review Melanoma is a highly aggressive skin malignancy with increasing incidence and mortality worldwide. Among its key genetic alterations, NRAS mutations occur in approximately 15–25% of melanomas, defining a distinct molecular subset associated with aggressive tumor behavior and poor prognosis. Unlike BRAF mutations, NRAS alterations remain largely undruggable, posing significant therapeutic challenges. This review examines the histotype-specific distribution of NRAS mutations in melanoma and discusses their molecular and clinical implications. Recent Findings Most NRAS mutations involve codon 61 and result in constitutive activation of the MAPK and PI3K signaling pathways, thereby promoting tumorigenesis and disease progression. Although NRAS-mutant melanomas are associated with an immunosuppressive tumor microenvironment, they also exhibit high immunogenicity, suggesting potential sensitivity to immune checkpoint inhibitors (ICIs). To further characterize the molecular landscape of NRAS-mutant melanoma, we analyzed data from the Catalogue of Somatic Mutations in Cancer (COSMIC), providing insights into the prevalence, distribution, co-mutation patterns, and functional consequences of NRAS alterations across different melanoma histotypes. Summary NRAS mutations represent a major driver of melanoma progression and define a biologically and clinically distinct subset of the disease. Despite encouraging responses to immunotherapy, clinical outcomes remain suboptimal, highlighting the need for novel therapeutic approaches. A deeper understanding of NRAS-driven oncogenesis, histotype-specific mutation patterns, and their impact on therapeutic response is essential for advancing precision medicine and improving outcomes for patients with melanoma.