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• W2803877013 abstract "BRAF is a serine/threonine-protein kinase in the MAPK/ERK signaling pathway, which is often activated by somatic point mutations in various cancers (Davies et al., 2002Davies H. Bignell G.R. Cox C. Stephens P. Edkins S. Clegg S. et al.Mutations of the BRAF gene in human cancer.Nature. 2002; 417: 949-954Crossref PubMed Scopus (8270) Google Scholar). About 40–60% of all malignant melanomas (MMs) carry BRAF mutations and ∼90% of these are the V600E type with an increased kinase activity (Chapman et al., 2011Chapman P.B. Hauschild A. Robert C. Haanen J.B. Ascierto P. Larkin J. et al.Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011; 364: 2507-2516Crossref PubMed Scopus (6112) Google Scholar, Davies et al., 2002Davies H. Bignell G.R. Cox C. Stephens P. Edkins S. Clegg S. et al.Mutations of the BRAF gene in human cancer.Nature. 2002; 417: 949-954Crossref PubMed Scopus (8270) Google Scholar). Because BRAF mutations are more frequent in benign nevi than in MMs (Pollock et al., 2003Pollock P.M. Harper U.L. Hansen K.S. Yudt L.M. Stark M. Robbins C.M. et al.High frequency of BRAF mutations in nevi.Nat Genet. 2003; 33: 19-20Crossref PubMed Scopus (1358) Google Scholar, Poynter et al., 2006Poynter J.N. Elder J.T. Fullen D.R. Nair R.P. Soengas M.S. Johnson T.M. et al.BRAF and NRAS mutations in melanoma and melanocytic nevi.Melanoma Res. 2006; 16: 267-273Crossref PubMed Scopus (195) Google Scholar, Shain et al., 2015Shain A.H. Yeh I. Kovalyshyn I. Sriharan A. Talevich E. Gagnon A. et al.The genetic evolution of melanoma from precursor lesions.N Engl J Med. 2015; 373: 1926-1936Crossref PubMed Scopus (621) Google Scholar, Shain and Bastian, 2016Shain A.H. Bastian B.C. From melanocytes to melanomas.Nat Rev Cancer. 2016; 16: 345-358Crossref PubMed Scopus (446) Google Scholar), they could be an initiating event in melanocytic proliferation (Patton et al., 2005Patton E.E. Widlund H.R. Kutok J.L. Kopani K.R. Amatruda J.F. Murphey R.D. et al.BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma.Curr Biol. 2005; 15: 249-254Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar, Poynter et al., 2006Poynter J.N. Elder J.T. Fullen D.R. Nair R.P. Soengas M.S. Johnson T.M. et al.BRAF and NRAS mutations in melanoma and melanocytic nevi.Melanoma Res. 2006; 16: 267-273Crossref PubMed Scopus (195) Google Scholar, Uribe et al., 2003Uribe P. Wistuba II, González S. BRAF mutation: a frequent event in benign, atypical, and malignant melanocytic lesions of the skin.Am J Dermatopathol. 2003; 25: 365-370Crossref PubMed Scopus (129) Google Scholar). To corroborate this possibility, we analyzed the BRAF V600E mutation rates in benign nevi as well as in lesions with histopathological characteristics of both benign nevi and MMs, designated as melanocytic tumors of uncertain malignant potential (MELTUMPs) (Barnhill et al., 2010Barnhill R.L. Cerroni L. Cook M. Elder D.E. Kerl H. LeBoit P.E. et al.State of the art, nomenclature, and points of consensus and controversy concerning benign melanocytic lesions: outcome of an international workshop.Adv Anat Pathol. 2010; 17: 73-90Crossref PubMed Scopus (57) Google Scholar, Elder and Xu, 2004Elder D.E. Xu X. The approach to the patient with a difficult melanocytic lesion.Pathology (Phila). 2004; 36: 428-434Scopus (108) Google Scholar). The histopathological definition of each lesion was established by at least two experienced dermatopathologists. This study of formalin-fixed, paraffin-embedded tissues from 45 MELTUMPs and 40 benign nevi (34 acquired melanocytic nevi, 3 congenital nevi, and 3 Clark’s nevi; Supplementary Table S1 online) was approved by the ethics committee of the University of Freiburg Medical Center (ethics vote 324/09). Under German law, written consent from the patients was not required because the material used had been collected for diagnostic and therapeutic purposes in the years 2006–2011 in the archives of the Institute for Surgical Pathology, University Hospital Freiburg and used for this study in pseudonymized form. All 85 samples were stained with the anti-BRAF V600E (clone VE1) monoclonal antibody, followed by the DakoREAL Detection System (Dako, Glostrup, Denmark) (Figure 1) and analyzed on a modified immunoreactive score (IRS) of the one described by Remmele and Stegner, 1987Remmele W. Stegner H.E. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue.Pathol. 1987; 8: 138-140Google Scholar (Figure 1 and Supplementary Table S2 online). Additionally, the BRAF V600E allele-specific PCR (Arcaini et al., 2012Arcaini L. Zibellini S. Boveri E. Riboni R. Rattotti S. Varettoni M. et al.The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms.Blood. 2012; 119: 188-191Crossref PubMed Scopus (143) Google Scholar) was performed in 31 MELTUMPs and 24 benign nevi samples (Supplementary Materials and Methods online and Supplementary Figure S1 online) and the PCR fragments were analyzed using a Genetic Analyzer 3130xl (Applied Biosystems, Carlsbad, CA) (Figure 2a–2c ).Figure 2Detection of the BRAF V600E mutation frequency by IHC or AS-PCR. (a–c) The lesions of interest in the IHC stains are marked by black arrows. (a) A MELTUMP that was positive for BRAF V600E in IHC (IRS n = 4), but not in the AS-PCR (scale bar = 25 μm). (b) Compound congenital nevus that was positive for the BRAF V600E mutation in IHC (IRS n = 12) and AS-PCR (scale bar = 50 μm). (c) MELTUMP that tested positive for the wild-type BRAF in IHC (IRS n = 0) and AS-PCR (scale bar = 100 μm). (d) Depiction of the final mutation status determined through one or both of our applied methods (AS-PCR and IHC) for all lesions. AS, allele-specific; bp, base pairs; IHC, immunohistochemistry; IRS, immunoreactive score; MUT, BRAF V600E mutation–specific primer; MELTUMP, melanocytic tumor of uncertain malignant potential; RFU, relative fluorescence unit; V600E, BRAF V600E; WT, wild-type BRAF.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The immunohistochemistry with the VE1 monoclonal antibody produced at least one interpretable stain for all 40 nevi and for 43 of 45 MELTUMPs and the BRAF V600E mutations were detected in 70.0% (28 of 40) of nevi and 51.2% (22 of 43) of MELTUMPs. The allele-specific PCR produced a valid result for all 55 tested lesions, with 62.5% (15 of 24) of the nevi and 51.6% (16 of 31) of MELTUMPs being positive for the BRAF V600E mutation. The overall mutation status of each lesion was defined as positive if at least one method detected the BRAF V600E mutation (Figure 2d). The overall BRAF V600E mutation rate in nevi was 70.0% (28 of 40) and higher than that in MELTUMPs—51.1% (23 of 45), but this difference (P = 0.083) (two-sided Fisher's exact test) was not statistically significant. The male-to-female ratio for all 85 lesions was 42:43, and the mean patient’s age at the time of tissue excision was 45.4 years. Melanocytic lesions located on the leg were significantly more frequently associated with the wild-type BRAF (P = 0.00138), whereas trunk lesions were significantly more likely to be BRAF V600E–mutated (P = 0.00677). MELTUMPs located on the trunk were significantly more likely to possess the BRAF V600E mutation than MELTUMPs located elsewhere (P = 0.0419). The age difference between BRAF V600E–positive MELTUMP patients (46.3 years) and MELTUMP patients with wild-type BRAF (52 years) was not statistically significant (P = 0.241). However, the mutated V600E allele was significantly more likely (P = 0.00502) to be present in men’s nevi than in women’s nevi, and significantly less likely (P = 0.00299) in nevi on the leg than in nevi elsewhere. Our results showing that the BRAF V600E mutation rate in MELTUMPs (51.1%) is lower than that of benign nevi (70%) are consistent with previously published data (Pollock et al., 2003Pollock P.M. Harper U.L. Hansen K.S. Yudt L.M. Stark M. Robbins C.M. et al.High frequency of BRAF mutations in nevi.Nat Genet. 2003; 33: 19-20Crossref PubMed Scopus (1358) Google Scholar, Poynter et al., 2006Poynter J.N. Elder J.T. Fullen D.R. Nair R.P. Soengas M.S. Johnson T.M. et al.BRAF and NRAS mutations in melanoma and melanocytic nevi.Melanoma Res. 2006; 16: 267-273Crossref PubMed Scopus (195) Google Scholar, Shain et al., 2015Shain A.H. Yeh I. Kovalyshyn I. Sriharan A. Talevich E. Gagnon A. et al.The genetic evolution of melanoma from precursor lesions.N Engl J Med. 2015; 373: 1926-1936Crossref PubMed Scopus (621) Google Scholar, Shain and Bastian, 2016Shain A.H. Bastian B.C. From melanocytes to melanomas.Nat Rev Cancer. 2016; 16: 345-358Crossref PubMed Scopus (446) Google Scholar, Uribe et al., 2003Uribe P. Wistuba II, González S. BRAF mutation: a frequent event in benign, atypical, and malignant melanocytic lesions of the skin.Am J Dermatopathol. 2003; 25: 365-370Crossref PubMed Scopus (129) Google Scholar) and compatible with the idea that the BRAF mutation might be an early step in melanocytic transformation (Uribe et al., 2003Uribe P. Wistuba II, González S. BRAF mutation: a frequent event in benign, atypical, and malignant melanocytic lesions of the skin.Am J Dermatopathol. 2003; 25: 365-370Crossref PubMed Scopus (129) Google Scholar). In fact, Shain et al., 2015Shain A.H. Yeh I. Kovalyshyn I. Sriharan A. Talevich E. Gagnon A. et al.The genetic evolution of melanoma from precursor lesions.N Engl J Med. 2015; 373: 1926-1936Crossref PubMed Scopus (621) Google Scholar concluded that the intermediate lesions are a biologically distinct group with unique genetic markers—such as frequent TERT promoter mutations, NRAS or the BRAF V600K mutations rather than the BRAF V600E—that differentiate them from benign nevi and MMs (Shain et al., 2015Shain A.H. Yeh I. Kovalyshyn I. Sriharan A. Talevich E. Gagnon A. et al.The genetic evolution of melanoma from precursor lesions.N Engl J Med. 2015; 373: 1926-1936Crossref PubMed Scopus (621) Google Scholar, Shain and Bastian, 2016Shain A.H. Bastian B.C. From melanocytes to melanomas.Nat Rev Cancer. 2016; 16: 345-358Crossref PubMed Scopus (446) Google Scholar). Consistent with these findings, in a zebrafish model, the BRAF V600E mutation led to benign melanocytic proliferation, requiring an additional p53 mutation for melanoma development (Patton et al., 2005Patton E.E. Widlund H.R. Kutok J.L. Kopani K.R. Amatruda J.F. Murphey R.D. et al.BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma.Curr Biol. 2005; 15: 249-254Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar). BRAF V600E–mutated lesions were significantly more frequently found on the trunk, a location often associated with intermitted sun exposure, than elsewhere. This observation was also made by others in MMs (Liu et al., 2006Liu W. Kelly J.W. Trivett M. Murray W.K. Dowling J.P. Wolfe R. et al.Distinct clinical and pathological features are associated with the BRAFT1799A(V600E) mutation in primary melanoma.J Invest Dermatol. 2006; 127: 900-905Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, Long et al., 2011Long G.V. Menzies A.M. Nagrial A.M. Haydu L.E. Hamilton A.L. Mann G.J. et al.Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.J Clin Oncol. 2011; 29: 1239-1246Crossref PubMed Scopus (825) Google Scholar), as well as in benign nevi (Karram et al., 2013Karram S. Novy M. Saroufim M. Loya A. Taraif S. Houreih M.A. et al.Predictors of BRAF mutation in melanocytic nevi: analysis across regions with different UV radiation exposure.Am J Dermatopathol. 2013; 35: 412-418Crossref PubMed Scopus (24) Google Scholar). In agreement with Karram et al., 2013Karram S. Novy M. Saroufim M. Loya A. Taraif S. Houreih M.A. et al.Predictors of BRAF mutation in melanocytic nevi: analysis across regions with different UV radiation exposure.Am J Dermatopathol. 2013; 35: 412-418Crossref PubMed Scopus (24) Google Scholar, the BRAF V600E–mutated melanocytic lesions were significantly less frequently located on the leg. Contrastingly, either no association between the BRAF V600E status and location on the extremities or positive correlations were reported in MMs (Liu et al., 2006Liu W. Kelly J.W. Trivett M. Murray W.K. Dowling J.P. Wolfe R. et al.Distinct clinical and pathological features are associated with the BRAFT1799A(V600E) mutation in primary melanoma.J Invest Dermatol. 2006; 127: 900-905Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, Long et al., 2011Long G.V. Menzies A.M. Nagrial A.M. Haydu L.E. Hamilton A.L. Mann G.J. et al.Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.J Clin Oncol. 2011; 29: 1239-1246Crossref PubMed Scopus (825) Google Scholar). Although the age differences among all our defined patient groups were statistically insignificant, at the time of diagnosis, patients with BRAF V600E–mutated lesions appeared to be slightly younger than patients with BRAF wild-type lesions similar to previous MM studies (Liu et al., 2006Liu W. Kelly J.W. Trivett M. Murray W.K. Dowling J.P. Wolfe R. et al.Distinct clinical and pathological features are associated with the BRAFT1799A(V600E) mutation in primary melanoma.J Invest Dermatol. 2006; 127: 900-905Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, Long et al., 2011Long G.V. Menzies A.M. Nagrial A.M. Haydu L.E. Hamilton A.L. Mann G.J. et al.Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.J Clin Oncol. 2011; 29: 1239-1246Crossref PubMed Scopus (825) Google Scholar). Thus, it appears that the BRAF V600E mutation might inversely reflect the degree of sun-induced skin damage (Landi et al., 2006Landi M.T. Bauer J. Pfeiffer R.M. Elder D.E. Hulley B. Minghetti P. et al.MC1R germline variants confer risk for BRAF-mutant melanoma.Science. 2006; 313: 521-522Crossref PubMed Scopus (269) Google Scholar, Liu et al., 2006Liu W. Kelly J.W. Trivett M. Murray W.K. Dowling J.P. Wolfe R. et al.Distinct clinical and pathological features are associated with the BRAFT1799A(V600E) mutation in primary melanoma.J Invest Dermatol. 2006; 127: 900-905Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar) that is likely to be higher in older people (Schäfer et al., 2006Schäfer T. Merkl J. Klemm E. Wichmann H.-E. Ring J. The epidemiology of nevi and signs of skin aging in the adult general population: results of the KORA-survey 2000.J Invest Dermatol. 2006; 126: 1490-1496Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). In the nevi subgroup, men had significantly more BRAF V600E–mutated nevi than women. This sex-dependent difference has not been noted in previous studies of MMs or benign nevi (Karram et al., 2013Karram S. Novy M. Saroufim M. Loya A. Taraif S. Houreih M.A. et al.Predictors of BRAF mutation in melanocytic nevi: analysis across regions with different UV radiation exposure.Am J Dermatopathol. 2013; 35: 412-418Crossref PubMed Scopus (24) Google Scholar, Uribe et al., 2003Uribe P. Wistuba II, González S. BRAF mutation: a frequent event in benign, atypical, and malignant melanocytic lesions of the skin.Am J Dermatopathol. 2003; 25: 365-370Crossref PubMed Scopus (129) Google Scholar). In conclusion, BRAF-mutated melanocytic lesions, especially MELTUMPs, are significantly more commonly located on the trunk and tend to occur at a younger age. MELTUMPs have a lower BRAF mutation frequency than benign nevi, which is compatible with genetic concepts where the BRAF mutation might be an event leading to cell proliferation of melanocytes, but not to their malignant transformation. Andreas von Deimling, is the inventor of the VE1 monoclonal antibody, which is commercially available. The remaining authors state no conflict of interest. We thank Marie Follo, PhD, for reading the manuscript. Jose Villacorta Hidalgo was supported by a PhD scholarship from Deutscher Akademischer Austauschdienst. The laboratory of PF is supported by a grant from Deutsche Forschungsgemeinschaft (SFB 1160-Z1). Download .pdf (.07 MB) Help with pdf files Supplementary Data" @default.
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• W2803877013 title "BRAF V600E Mutations in Nevi and Melanocytic Tumors of Uncertain Malignant Potential" @default.
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