engleski

SIGNIFICANCE OF NRAS MUTATIONS IN METASTATIC MELANOMA

INTRODUCTION: Treatment for metastatic melanoma (MM) still remains a challenge since long- term survival is poor and median overall survival is less than twelve months. Detection of BRAF mutation in melanomas implemented molecular targeted therapy. The BRAF gene encodes a pro- tein which plays a role in the control of cell proliferation, differentiation, inflammatory responses and apoptosis via the mitogen activated protein kinase (MAPK) pathway. Approximately 40-60% of primary melanomas of sun-exposed skin origin harbor a BRAF mutation and those patients are candidates for therapy with BRAF inhibitors. Patients with BRAF mutated melanomas have improved response rate and progression-free survival after targeted therapy. NRAS protein also belongs to a MAPK pathway, but is involved in several other pathways like WNT and PIK3 and its gene mutation results in constitutive activation of those pathways. NRAS mutation occurs in 15-20% of primary melanomas, with uncertain significance, where is usually mutually exclusive with BRAF mutation. In contrast to BRAF, NRAS mutations occur in all melano- mas of non-uveal sites and are rarely present in benign melanocytic nevi. MATERIAL AND METHOD: A pilot study was conducted on sixteen MM. DNA was isolated from FFPE tissue. BRAF and NRAS mutations were detected by real-time PCR, using Cobas BRAF/NRAS Mutation Test designed to detect 11 mutations of BRAF and 25 mutations of NRAS gene. RESULTS: Out of sixteen patients, 75% were male with a median age of 53.5 years and 25% were women with median age of 69.5 years at the time of first diagnosis. BRAF mutation was found in eight cases (50%), seven in male and one in female patients. Eight melanomas were BRAF non-mutated (wild type), but five of them (62.5%) harbor NRAS mutation. Patients with BRAF mutation were younger (median age 46 years) than patients with NRAS mutated MM (median age 60 years). BRAF mutation was more frequently found in metastases from SSM (43%), while NRAS was associated with nodular melanoma (40%). We found no difference in clinical characteristics between BRAF and NRAS mutated MM. Only three patients (18.8%) were wild type of both genes. DISCUSSION: Recent literature reports that the mutant NRAS melanoma has a more aggressive behavior and poorer outcome compared to non-NRAS mutant melanoma. No therapeutic agents have yet been approved for NRAS mutation melanoma. However, NRAS driven melanomas might have few therapeutic options like small molecule MEK inhibitors, small interfering RNAs or immune-based therapy. CONCLUSION: All BRAF-wild type metastatic melanomas should be additionally tested for NRAS mutations to select patients who also might benefit from targeted therapy.

metastatic melanoma, BRAF, NRAS

nije evidentirano