Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma

The management of melanoma has evolved due to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAF(V600) (36%), NRAS (21%), TP53 (16%), BRAF(Non-V600) (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent event in tumors with BRAF(V600) and NRAS mutations. Melanomas with BRAF(Non-V600) mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAF(V600) mutations (1.6%). The prevalence of BRAF(V600) and KIT mutations were significantly associated with melanoma subtypes, and BRAF(V600) and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAF(V600) and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.