BRAF and NRAS mutations in Russian melanoma patients: results of a nationwide study.

Distribution of actionable mutations in melanoma may show considerable geographic variations. Given the importance of genetic testing for the proper use of targeted drugs, we carried out the first-in-Russia nationwide molecular epidemiological study for melanoma. Sanger sequencing analysis for BRAF (exon 15) and NRAS (exons 2-4) genes was carried out for patients with the stage IIIB or IV disease from 46 cancer centers located throughout the country. BRAF mutations were identified in 625/1034 (60.4%) melanoma samples. BRAF c.1799T>A (p.V600E) substitution was the most prevalent, being detected in 561/1034 (54.3%) tumors. Non-V600E mutations constituted about 10% of activating BRAF genetic lesions (64/625, 10.2%), with a clear prevalence of c.1798_1799GT>AA (p.V600K) variant (52 tumors) and noticeable occurrence of c.1798_1799GT>AG (p.V600R) allele (five tumors). BRAF V600E mutations were associated with younger patient age and localization of melanoma on sun-protected areas of the skin, whereas BRAF V600K substitutions were characteristic of elderly patients and occurred more often at the chronically sun-exposed regions of the body. Activating NRAS mutations were detected in 86/601 (14.3%) of samples analyzed, with 79 events affecting codon 61 and seven mutations detected in codons 12 or 13. Six types of distinct NRAS codon 61 substitutions were identified, with c.181C>A (p.Q61K), c.182A>G (p.Q61R), and c.182A>T (p.Q61L) being frequent and c.181_182CA>TT (p.Q61L), c.183A>T (p.Q61H), and c.183A>C (p.Q61H) being rare. An age-related increase in the frequency of NRAS mutations was observed. Multiplicity and clinical distribution of BRAF and NRAS mutations have to be taken into account while considering molecular testing for melanoma patients. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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