title: Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma.
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.
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Siroy
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Genevieve M
authors.initials: GM
authors.lastname: Boland
authors.affiliation: Department of Biostatistics, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Denái R
authors.initials: DR
authors.lastname: Milton
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Silva
authors.initials: S
authors.lastname: Frankian
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Malke
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Haydu
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA; Department of Dermatology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tetzlaff
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA; Department of Dermatology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Doina
authors.initials: D
authors.lastname: Ivan
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA; Department of Dermatology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Torres-Cabala
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Curry
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Sinchita
authors.initials: S
authors.lastname: Roy-Chowdhuri
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA; Department of Cancer Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Rodabe N
authors.initials: RN
authors.lastname: Amaria
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Sapna P
authors.initials: SP
authors.lastname: Patel
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Papadopoulos
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Agop
authors.initials: A
authors.lastname: Bedikian
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Wen-Jen
authors.initials: WJ
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Adi
authors.initials: A
authors.lastname: Diab
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA; Department of Systems Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Woodman
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.affiliation: Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Keyur P
authors.initials: KP
authors.lastname: Patel
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Kenna R
authors.initials: KR
authors.lastname: Shaw
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mendelsohn
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA; Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Department of Hematopathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Routbort
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA; Department of Dermatology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Melanoma Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA; Department of Systems Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA. Electronic address: MDavies@mdanderson.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
mesh_terms: D020558:GTP Phosphohydrolases / Q000235:genetics; D016158:Genes, p53; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human