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. 2015 Feb;135(2):508-515.
doi: 10.1038/jid.2014.366. Epub 2014 Aug 22.

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

Alan E Siroy  1 , Genevieve M Boland  2 , Denái R Milton  3 , Jason Roszik  4 , Silva Frankian  4 , Jared Malke  2 , Lauren Haydu  2 , Victor G Prieto  5 , Michael Tetzlaff  1 , Doina Ivan  5 , Wei-Lien Wang  1 , Carlos Torres-Cabala  5 , Jonathan Curry  1 , Sinchita Roy-Chowdhuri  1 , Russell Broaddus  1 , Asif Rashid  1 , John Stewart  1 , Jeffrey E Gershenwald  6 , Rodabe N Amaria  4 , Sapna P Patel  4 , Nicholas E Papadopoulos  4 , Agop Bedikian  4 , Wen-Jen Hwu  4 , Patrick Hwu  4 , Adi Diab  4 , Scott E Woodman  7 , Kenneth D Aldape  1 , Rajyalakshmi Luthra  8 , Keyur P Patel  8 , Kenna R Shaw  9 , Gordon B Mills  9 , John Mendelsohn  10 , Funda Meric-Bernstam  11 , Kevin B Kim  4 , Mark J Routbort  8 , Alexander J Lazar  5 , Michael A Davies  12
Affiliations

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

Alan E Siroy et al. J Invest Dermatol. 2015 Feb.

Abstract

The management of melanoma has evolved owing 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 BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-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 events in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 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 BRAFV600 and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.

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Conflict of interest statement

Conflict of Interest: JM serves on the Board of Merrimack Pharmaceuticals. The remaining authors state no conflict of interest.

Figures

Figure 1
Figure 1
Prevalence of detected gene mutations by melanoma subtype. Panels show the rate of gene mutations observed in (a) cutaneous melanomas, (n=484); (b) unknown primary melanomas, (n=104); (c) acral melanomas, (n=54); and (d) mucosal melanoma, (n=43).
Figure 2
Figure 2
Prevalence of concurrent mutations among melanomas with common gene mutations. Panels show the rate of concurrent mutations present in melanomas with (a) BRAFV600; (b) BRAFNon-V600; (c) NRAS; and (d) KIT.
Figure 3
Figure 3
Associations of mutations with clinical subtypes and primary tumor location. (a) Gene mutation rates in different melanoma subtypes (Black, cutaneous; Striped, acral; White, mucosal, Spotted, unknown primary). * BRAFV600 mutations (p<0.001) were significantly associated with cutaneous and unknown primary melanomas, whereas KIT mutations (p<0.001) were significantly associated with acral and mucosal melanomas. (b) Primary tumor location of prevalent gene mutations in cutaneous melanomas (Black, head/neck; Striped, trunk; White, extremity). * BRAFV600 mutations were significantly associated with the trunk compared to the head/neck (p=0.0004), while TP53 mutations were significantly associated with the head/neck compared to the trunk (p=0.03) or extremities (p<0.0001).
Figure 4
Figure 4
Mutations detected in cutaneous and unknown primary melanomas without a BRAFV600 or NRAS mutation (n=113).
See this image and copyright information in PMC

Comment in

  • Panel sequencing melanomas.
    Griewank KG, Schadendorf D. Griewank KG, et al. J Invest Dermatol. 2015 Feb;135(2):335-336. doi: 10.1038/jid.2014.420. J Invest Dermatol. 2015. PMID: 25573045

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