Lokhandwala P.M.LI-HUI TSENGRodriguez E.Zheng G.Pallavajjalla A.Gocke C.D.Eshleman J.R.Lin M.-T.2022-03-102022-03-1020191471-2407https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069269696&doi=10.1186%2fs12885-019-5864-1&partnerID=40&md5=b7d31defccf12111105a04c1ea1b70afhttps://scholars.lib.ntu.edu.tw/handle/123456789/597080Background: Analysis of melanomas for actionable mutations has become the standard of care. Recently, a classification scheme has been proposed that categorizes BRAF mutations based on their mechanisms for activation of the MAPK pathway. Methods: In this analysis BRAF, KIT, NRAS, and PIK3CA mutations were examined by next generation sequencing (NGS) in 446 melanomas in a clinical diagnostic setting. KRAS and HRAS were also analyzed to elucidate coexisting BRAF and RAS mutations. BRAF mutations were categorized into class-1 (kinase-activated, codon 600), class-2 (kinase-activated, non-codon 600) and class-3 (kinase-impaired), based on the newly proposed classification scheme. Results: NGS demonstrated high analytic sensitivity. Among 355 mutations detected, variant allele frequencies were 2-5% in 21 (5.9%) mutations and 2-10% in 47 (13%) mutations. Mutations were detected in BRAF (42%), NRAS (25%), KIT (4.9%) and PIK3CA (2.7%). The incidence of class-1, class-2 and class-3 mutations were 33% (26% p.V600E and 6.1% p.V600K), 3.1 and 4.9% respectively. With a broader reportable range of NGS, class-1, class-2 and class-3 mutations accounted for 77, 7.4 and 12% of all BRAF mutations. Class-3 mutations, commonly affecting codons 594, 466 and 467, showed a higher incidence of coexisting RAS mutations, consistent with their RAS-dependent signaling. Significant association with old age and primary tumors of head/neck/upper back suggest chronic solar damage as a contributing factor for melanomas harboring BRAF p.V600K or class-3 mutations. Conclusion: This study categorizes the range, frequency, coexisting driver mutations and clinical characteristics of the three classes of BRAF mutations in a large cohort of melanomas in a clinical diagnostic setting. Further prospective studies are warranted to elucidate the clinical outcomes and benefits of newly developed targeted therapy in melanoma patients carrying each class of BRAF mutation. ? 2019 The Author(s).BRAF; Categorization; Kinase-impaired; Melanoma; NRAS[SDGs]SDG3adult; Article; BRAF gene; cancer diagnosis; cancer therapy; clinical outcome; codon; cohort analysis; female; gene frequency; gene mutation; genetic analysis; genetic transduction; genetic variability; head and neck cancer; human; KIT gene; light damage; major clinical study; male; melanoma; middle aged; mutation rate; mutational analysis; next generation sequencing; oncogene; oncogene H ras; oncogene K ras; oncogene N ras; PIK3CA gene; primary tumor; retrospective study; risk factor; sensitivity analysis; signal transduction; sun exposure; adverse event; aged; carcinogenesis; genetics; high throughput sequencing; MAPK signaling; melanoma; metabolism; mutation; sensitivity and specificity; skin tumor; sunlight; B Raf kinase; BRAF protein, human; guanosine triphosphatase; membrane protein; NRAS protein, human; Aged; Carcinogenesis; Codon; Female; Gene Frequency; GTP Phosphohydrolases; High-Throughput Nucleotide Sequencing; Humans; Male; MAP Kinase Signaling System; Melanoma; Membrane Proteins; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Retrospective Studies; Sensitivity and Specificity; Skin Neoplasms; Sunlightjournal article10.1186/s12885-019-5864-1312775842-s2.0-85069269696