The DecisionDx-CMSeq test evaluates mutations in exon 15 of BRAF, where the most common and clinically actionable mutations occur. BRAF is the most commonly mutated gene in melanoma with approximately 40-50% of cases harboring mutations (Hayward 2017; TCGA 2015). Mutations in BRAF are activating events and lead to stimulation of the MAPK pathway (Davies 2002; Holderfield 2012). The V600 codon is the most commonly mutated codon in the gene. Specifically, the V600E variant is present in ~90% of tumors with a BRAF mutation (Cheng 2017; Richtig 2017). There are FDA-approved BRAF and MEK inhibitors for patients with unresectable BRAF V600E and V600K-mutant Stage III or IV melanoma. Additionally, a recent clinical trial showed that combination targeted therapy is effective for resected Stage III patients, leading to the FDA approval of these therapies for resected Stage III patients with BRAF V600E/K-mutant melanoma. Less common mutations, such as V600R/D and nonV600, are also of potential significance as there are ongoing clinical trials enrolling patients with these mutations.

The DecisionDx-CMSeq test identifies mutations in codons Q61, G12, and G13 of NRAS, which occur in approximately 20% of cutaneous melanomas and also lead to MAPK pathway activation. Q61 mutations are the most common (~80-90%) (Posch 2016; Schubbert 2007; Fedorenko 2013). Secondary NRAS mutations have a role in the development of BRAF inhibitor resistance (Long 2014; Rizos 2014). While there are currently no FDA-approved targeted therapies for NRAS-mutant melanoma, a few clinical trials with MEK inhibitors have shown promise (Dummer 2017; Johnson 2015; Koelblinger 2017). There are some data to suggest that treatment with therapies that target NRAS may be an effective option. There are several ongoing clinical trials for the treatment of NRAS-mutant melanoma and these may be important to consider for patients whose tumors harbor these mutations.

The DecisionDx-CMSeq test identifies mutations across various positions in the KIT gene: exons 2, 9-11, 13-15 and 17 which include the most common mutations (L576P, V559A, W557R, V560D, K642E, D820Y, D816H, N822K). KIT mutations typically result in constitutive kinase activity, directly or indirectly, and subsequent downstream pathway activation (Reddy 2017). Mutations in KIT are less common (<10%) than BRAF and NRAS across melanoma broadly but are frequently found in acral, mucosal, and chronically sun-damaged melanoma (Dumaz 2015; Curtin 2006; Gong 2018). While there are currently no FDA-approved targeted therapies for KIT-mutant melanoma, clinical trials with tyrosine kinase inhibitors or MEK inhibitors have shown promise for some KIT-mutant melanoma (Hodi 2008; Lutzky 2008; Carvajal 2011; Guo 2011; Hodi 2013). There are several ongoing clinical trials for the treatment of KIT-mutant melanoma and these may be important to consider for patients whose tumors harbor these mutations.