Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencing
Abstract Background 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 m...
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| Format: | Article |
| Language: | English |
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BMC
2019-07-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-019-5864-1 |
| _version_ | 1818852196151721984 |
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| author | Parvez M. Lokhandwala Li-Hui Tseng Erika Rodriguez Gang Zheng Aparna Pallavajjalla Christopher D. Gocke James R. Eshleman Ming-Tseh Lin |
| author_facet | Parvez M. Lokhandwala Li-Hui Tseng Erika Rodriguez Gang Zheng Aparna Pallavajjalla Christopher D. Gocke James R. Eshleman Ming-Tseh Lin |
| author_sort | Parvez M. Lokhandwala |
| collection | DOAJ |
| description | Abstract Background 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. |
| first_indexed | 2024-12-19T07:17:04Z |
| format | Article |
| id | doaj.art-92adc55eda7d4741b209a0141fcd7dab |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-19T07:17:04Z |
| publishDate | 2019-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-92adc55eda7d4741b209a0141fcd7dab2022-12-21T20:31:02ZengBMCBMC Cancer1471-24072019-07-0119111010.1186/s12885-019-5864-1Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencingParvez M. Lokhandwala0Li-Hui Tseng1Erika Rodriguez2Gang Zheng3Aparna Pallavajjalla4Christopher D. Gocke5James R. Eshleman6Ming-Tseh Lin7Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University School of MedicineDepartment of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University School of MedicineAbstract Background 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.http://link.springer.com/article/10.1186/s12885-019-5864-1BRAFNRASMelanomaKinase-impairedCategorization |
| spellingShingle | Parvez M. Lokhandwala Li-Hui Tseng Erika Rodriguez Gang Zheng Aparna Pallavajjalla Christopher D. Gocke James R. Eshleman Ming-Tseh Lin Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencing BMC Cancer BRAF NRAS Melanoma Kinase-impaired Categorization |
| title | Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencing |
| title_full | Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencing |
| title_fullStr | Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencing |
| title_full_unstemmed | Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencing |
| title_short | Clinical mutational profiling and categorization of BRAF mutations in melanomas using next generation sequencing |
| title_sort | clinical mutational profiling and categorization of braf mutations in melanomas using next generation sequencing |
| topic | BRAF NRAS Melanoma Kinase-impaired Categorization |
| url | http://link.springer.com/article/10.1186/s12885-019-5864-1 |
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