NRAS Mutations in Different Melanoma Histotypes: Molecular and Clinical Implications
- 1Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Traversa La Crucca 3, Sassari, 07100 Italy
- 2Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca 3, Sassari, 07100 Italy
- 3Dipartimento di Medicina, Chirurgia e Farmacia, Università degli Studi di Sassari, Viale San Pietro 43, Sassari, 07100 Italy
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.
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BibTeX
@article{pisano2026nras,
title = {{NRAS Mutations in Different Melanoma Histotypes: Molecular and Clinical Implications}},
author = {Marina Pisano and Silvia Tore and Sara Demartis and Roberto Nico Dallocchio and Stefania Casula and Maria Colombino and Antonella Manca and Manuela Usai and Luca Nuvoli and Giuseppe Palmieri and Milena Casula},
journal = {Current Oncology Reports},
year = {2026},
month = oct,
doi = {10.1007/s11912-026-01851-x},
url = {https://doi.org/10.1007/s11912-026-01851-x},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - NRAS Mutations in Different Melanoma Histotypes: Molecular and Clinical Implications
AU - Marina Pisano
AU - Silvia Tore
AU - Sara Demartis
AU - Roberto Nico Dallocchio
AU - Stefania Casula
AU - Maria Colombino
AU - Antonella Manca
AU - Manuela Usai
AU - Luca Nuvoli
AU - Giuseppe Palmieri
AU - Milena Casula
PY - 2026
DA - 2026/10/26
JO - Current Oncology Reports
DO - 10.1007/s11912-026-01851-x
UR - https://doi.org/10.1007/s11912-026-01851-x
AB - 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.
SN - 1523-3790
SN - 1534-6269
ER -