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Melanoma is the most aggressive form of skin cancer and the leading cause of death from cutaneous tumors. Several studies have associated alterations in the TERT promoter region (pTERT) with gene overexpression, aggressiveness and poor prognosis of the disease. The aim of this study was to clarify the role of pTERT molecular status in paired samples of primary melanoma and metastasis using tissue and plasma to establish a correlation with disease progression and survival. A total of 88 FFPE tissue samples from 53 patients with advanced melanoma were analyzed. Of these, 35 had paired samples. We also examined cfDNA samples from plasma of 25 patients. We detected a good correlation between primary tumors and metastases in pTERT mutation and methylation status. We were also able to identify pTERT mutations in plasma samples that correlated with mutational status in tissue samples. Interestingly, the C250T mutation was associated with worse survival and higher TERT mRNA expression, compared to the other most common mutation: C228T. In addition, hyper-methylation of the promoter region seems to be related to the progression of pTERT wild type (WT) patients. These results suggest that TERT gene alterations plays an important role during tumor progression, with the detection of the C250T mutation in tissue and plasma as a potential biomarker of poor prognosis in patients with advanced melanoma.
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ABSTRACT: We report a noteworthy case of a 10-year-old girl who presented with papular and nodular lesions on the skin that were clinically and histologically mistaken for progressive nodular histiocytosis. During the clinical management of the patient, the high lipid levels raised the suspicion of lipid metabolism disease and helped us to make the correct diagnosis of sitosterolemia. In sitosterolemia, proper management such as restriction of plant sterol intake and administration of cholesterol absorption inhibitor can improve prognosis.
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Histiocitosis , Fitosteroles , Enfermedades de la Piel , Xantomatosis , Niño , Colesterol , Femenino , Histiocitosis/diagnóstico , Humanos , Hipercolesterolemia , Enfermedades Intestinales , Errores Innatos del Metabolismo Lipídico , Fitosteroles/efectos adversos , Sitoesteroles/metabolismo , Enfermedades de la Piel/diagnóstico , Xantomatosis/diagnóstico , Xantomatosis/metabolismoRESUMEN
ABSTRACT: Giant cell tumor of soft tissue (GCTST) is a rare neoplasm genetically unrelated but histopathologically indistinguishable to its osseous counterpart. Histologically, GCTST is characterized as a multinodular proliferation of bland histiocytoid mononuclear cells intermixed with osteoclast-like giant cells. GCTST most commonly presents as a soft-tissue mass located in the extremities of middle-aged adults. In this report, we describe a case of a dermal GCTST arising in the periocular region of a 3-year-old girl. This is the youngest patient diagnosed with GCTST reported in the literature and is also singular because of its anatomic location: Only a handful of head and neck GCTSTs have been reported to date. Furthermore, GCTST most often presents as a superficial or deep soft-tissue mass and much less commonly as a dermal-based skin tumor, as was our case. On microscopic examination, the resected lesion demonstrated classical features including numerous osteoclast-like giant cells embedded in a background of mononuclear ovoid cells which displayed brisk mitotic activity and were surrounded by variable stromal hemorrhage. Tumor cells presented a vaguely fascicular arrangement. Immunohistochemical profile demonstrated positivity for smooth muscle actin and CD68 and negativity for desmin, myo-D1, S100, HMB-45, Melan-A, p16, and NKIC3. The unusual characteristics of this case emphasize the clinicopathologic heterogeneity of GCTST.
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Tumores de Células Gigantes/patología , Neoplasias de los Tejidos Blandos/patología , Preescolar , Cara/patología , Femenino , HumanosRESUMEN
PURPOSE: To retrospectively describe the clinical characteristics, management, and outcomes of four cases of orbital solitary fibrous tumor (SFT). In one patient, we present an ultrasonic aspirator system for tumor removal. METHODS: Four patients with orbital SFT were selected: one patient with orbital SFT, another patient with frontal and ethmoidal SFT and orbital affectation with high rates of recurrence, the third patient with frontal lobe SFT and orbital invasion with multiple recurrences, and the fourth case with a history of craniopharyngioma surgery and SFT located on the orbital apex. RESULTS: All cases showed proptosis, eye movement restriction, and, in three cases, visual acuity alteration. Different treatments were applied: in three cases, excision was performed, one of them with an ultrasonic aspirator system, and in the remaining case, an exenteration was done (in two cases, radiosurgery treatment was also applied). The immunohistochemical study revealed SFT, similar to hemangiopericytomas (HPCs). No recurrence has been observed after surgical treatment. CONCLUSION: The SFT is a spectrum of different tumors with similar histopathological characteristics. The use of immunohistochemical markers is very helpful in the diagnosis. The main problem of orbital involvement is the risk of damaging important structures adjacent to the tumor during the surgical removal. The ultrasonic aspirator system allows elimination of the tumor without damaging other orbital structures.
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Deep penetrating nevus (DPN) is an intradermal, sometimes compound benign melanocytic lesion, which involves the reticular dermis, occasionally reaching the subcutis, which can raise concern for melanoma both clinically and histologically. Recently, it has been genetically defined by the combination of MAPK activating and ß-catenin activating mutations. We sought to investigate genetic alterations in 2 cases of combined nevi of congenital melanocytic and DPN. Case 1 was a 16-year-old woman with a pigmented lesion on the trunk since birth, which was completely excised. Histopathological examination revealed a combined congenital nevus with a DPN. Comparative genomic hybridization showed no major genetic alterations, except for gain of 6q11.1 and point mutation of B-RAF V600E. Case 2 was a 62-year-old woman with a congenital pigmented lesion on the back. The lesion was diagnosed as a combined nevus of congenital and DPN. Comparative genomic hybridization showed no genetic alterations, and the NRAS Q61K was detected in both components. DPN is in most cases part of a combined nevus. Our cases showed strong and uniform nuclear expression of ß-catenin and cyclin D1 in the DPN component suggesting the evolution of the congenital nevus to the DPN clone by acquiring ß-catenin activating mutation.
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Biomarcadores de Tumor/genética , Mutación con Ganancia de Función , Nevo Pigmentado/congénito , Neoplasias Cutáneas/congénito , beta Catenina/genética , Adolescente , Biomarcadores de Tumor/análisis , Hibridación Genómica Comparativa , Ciclina D1/análisis , Femenino , GTP Fosfohidrolasas/genética , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Proteínas de la Membrana/genética , Persona de Mediana Edad , Invasividad Neoplásica , Nevo Pigmentado/química , Nevo Pigmentado/patología , Nevo Pigmentado/cirugía , Fenotipo , Mutación Puntual , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/química , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , beta Catenina/análisisRESUMEN
Langerhans cell histiocytosis (LCH) is a rare proliferative disorder, more frequent in children, characterized by an abnormal accumulation of Langerhans cells admixed with eosinophils, lymphocytes, neutrophils, and macrophages. The clinical presentation is variable and depends on whether a single or multiple organs are affected. Skin lesions are common in LCH (40% of cases) and represent a frequent form of presentation (in up to 80% of cases). Cutaneous manifestations of LCH are highly variable, frequently presenting as crusted papules or scaly seborrheic-like lesions localized in the scalp. We report the first case of a localized acral sclerosing LCH, a new form of LCH. This case highlights the broad and surprising form of presentation of LCH which may be overlooked and can significantly delay its diagnosis. The development of systemic disease may occur months to years after the initial skin presentation. Prompt diagnosis and treatment may prevent progression to systemic disease, as documented in some cases.
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Histiocitosis de Células de Langerhans/patología , Enfermedades de la Piel/patología , Adulto , Dedos/patología , Humanos , Masculino , Esclerosis/patologíaAsunto(s)
Alopecia/inducido químicamente , Productos Biológicos/efectos adversos , Certolizumab Pegol/efectos adversos , Psoriasis/inducido químicamente , Sacroileítis/tratamiento farmacológico , Alopecia/diagnóstico , Alopecia/patología , Productos Biológicos/administración & dosificación , Biopsia , Certolizumab Pegol/administración & dosificación , Sustitución de Medicamentos , Femenino , Humanos , Persona de Mediana Edad , Psoriasis/diagnóstico , Psoriasis/patología , Piel/efectos de los fármacos , Piel/patología , Ustekinumab/administración & dosificaciónRESUMEN
Congenital melanocytic nevi (CMN) are benign melanocytic proliferations that are usually present at birth. A somatic mosaicism for an NRAS point mutation is responsible for the several phenotypic abnormalities that may be associated with congenital nevi. We report the case of a 7-year-old boy with a proliferative nodule (PN) arising in a Giant CMN completely excised and with several visceral and intraspinal melanoma metastases with no evidence of primary cutaneous melanoma. The careful analysis of the clinical, morphologic, and molecular features allowed the distinction of between the benign PN (BPN) and the melanoma. The BPN showed a characteristic comparative genomic hybridization pattern with gains or losses of whole chromosomes, whereas the melanoma displayed gains or losses involving complex partial chromosomal copy number gains or losses. Leptomeningeal melanocytes are more susceptible to transformation by oncogenic NRAS than cutaneous melanocytes, and central nervous system melanomas are more common than cutaneous melanomas in the setting of CMN. Thus, it has been recommended to characterize the congenital disease in patients with 2 CMN at birth, independently of size and site, with a single magnetic resonance imaging screening younger than the age of 1 year.
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GTP Fosfohidrolasas/genética , Melanoma/genética , Proteínas de la Membrana/genética , Nevo Pigmentado/genética , Neoplasias Cutáneas/genética , Niño , Humanos , Masculino , Melanoma/patología , Mutación , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Nevo Pigmentado/patología , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours, and demonstrated that NTRK3 fusions constitutively activate the mitogen-activated protein kinase, phosphoinositide 3-kinase and phospholipase Cγ1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small-molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which no targeted options currently exist. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Receptor con Dominio Discoidina 2/genética , Proteínas Motoras Moleculares/genética , Cadenas Pesadas de Miosina/genética , Miosina Tipo V/genética , Nevo de Células Epitelioides y Fusiformes/enzimología , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Neoplasias Cutáneas/enzimología , Adolescente , Adulto , Anciano , Niño , Preescolar , Hibridación Genómica Comparativa , Receptor con Dominio Discoidina 2/metabolismo , Femenino , Humanos , Masculino , Melanoma/enzimología , Melanoma/genética , Melanoma/patología , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Motoras Moleculares/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Miosina Tipo V/metabolismo , Nevo de Células Epitelioides y Fusiformes/genética , Nevo de Células Epitelioides y Fusiformes/patología , Fusión de Oncogenes , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteínas Represoras/metabolismo , Análisis de Secuencia de ADN , Análisis de Secuencia de ARN , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteína ETS de Variante de Translocación 6RESUMEN
Recent advances in targeting BRAF mutations, which occur in roughly 50% of the melanomas, have improved response rates and overall survival in patients with advanced disease. With the increasingly extensive use of the drug, new, nonpreventable, cutaneous and noncutaneous toxicities keep arising as infrequent adverse effects. We report a 55-year-old man with a history of metastatic melanoma treated with the dabrafenib who presented, 10 months after the initiation of the treatment, with erythematous, slightly squamous, round plaques on his upper trunk and on his left upper arm. Two skin biopsies from the lesions revealed a granulomatous dermatitis in the superficial reticular dermis. One of them showed admixed abundant melanophages from tumoral melanosis. No melanoma cells were seen in any of the specimens. No interruption of the treatment was necessary. Our observation indicates that such a response may represent a positive immune activation triggered by BRAF inhibitors. The erythematous rash was initially concerning for progression of metastatic disease, which suggests that a close monitoring of the patients with advanced melanomas treated with vemurafenib is advisable to prevent unnecessary discontinuation of the therapy.
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Antineoplásicos/efectos adversos , Erupciones por Medicamentos/etiología , Eritema/inducido químicamente , Granuloma/inducido químicamente , Imidazoles/efectos adversos , Melanoma/tratamiento farmacológico , Oximas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Piel/efectos de los fármacos , Biopsia , Diagnóstico Diferencial , Erupciones por Medicamentos/patología , Eritema/patología , Granuloma/patología , Humanos , Masculino , Melanoma/enzimología , Melanoma/genética , Melanoma/secundario , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Piel/patología , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
We report the case of a 77-year-old diabetic patient with asymptomatic papular eruption developed over a cutaneous scar after the resection of a squamous cell carcinoma. Histological examination revealed a clear cell proliferation involving the secretory portion of the eccrine glands. This entity has been previously named as papular clear cell hyperplasia of the eccrine duct. This clear cell change might be caused by glycogen deposition because of diabetes. We postulate that papular clear cell hyperplasia could be a precursor lesion of clear cell syringoma.
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Glándulas Ecrinas/patología , Lesiones Precancerosas/patología , Anciano , Carcinoma de Células Escamosas/epidemiología , Cicatriz/patología , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Hiperplasia/patología , Neoplasias Cutáneas/epidemiología , Neoplasias de las Glándulas Sudoríparas/patología , Siringoma/patologíaRESUMEN
The era of targeted therapy has introduced a new therapeutic perspective for melanoma patients. Treatment with BRAFV600 inhibitors has improved overall and disease-free survival in metastatic melanoma patients whose tumors harbor BRAFV600 mutations. Although the BRAFV600E mutation appears to have a critical role in tumor initiation, its expression during tumor progression remains controversial. In fact, various authors claim that BRAFV600E heterogeneity is evident in melanoma tumors. Herein, we investigated the pattern of BRAFV600E expression in matched primary and metastatic samples from 140 patients. Using a combination of real-time PCR and immunohistochemical analyses, we demonstrated that BRAFV600E expression is homogeneous in melanoma tumors and hypothesized that the heterogeneity described by others might be attributable to technical issues when molecular methods are used. We also demonstrated the high efficiency of the anti-BRAFV600E VE1 antibody for the detection of BRAFV600E mutations in melanoma tumors.
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Melanoma/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumours with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumours lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K) and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.
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Reordenamiento Génico , Melanoma Experimental/genética , Nevo de Células Epitelioides y Fusiformes/genética , Fusión de Oncogenes , Proteínas Proto-Oncogénicas c-met/genética , Adulto , Animales , Línea Celular , Femenino , Humanos , Masculino , Ratones , Persona de Mediana EdadRESUMEN
Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK), we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17%, respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.
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Nevo de Células Epitelioides y Fusiformes/genética , Nevo de Células Epitelioides y Fusiformes/patología , Proteínas Tirosina Quinasas Receptoras/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Adolescente , Quinasa de Linfoma Anaplásico , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Genómica , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Persona de Mediana Edad , Nucleofosmina , Proteínas de Fusión Oncogénica/genética , Adulto JovenRESUMEN
Primary cutaneous spindle cell lymphoma is a unique morphologic variant of cutaneous B-cell follicle center lymphoma characterized by a prominent population of spindle-shaped, medium, and large B lymphocytes with a poorly formed storiform pattern.We report a case of a 35-year-old woman who presented with a well-defined erythematous plaque with 2 nodular, nontender nonscaling nonulcerated lesions on her right cheek mimicking acne rosacea. Microscopic examination revealed a tumor mainly centered in the reticular dermis and mostly composed of spindle-shaped large B lymphocytes exhibiting bizarre shapes with "boomerang-like" or "spermatozoa-like" appearance. The immunohistochemical staining demonstrated neoplastic lymphocytes positive for CD20, CD79α, and BCL-6, and negative for CD3, CD43, CD10, BCL-2, and MUM-1. These results supported the diagnosis of a follicle center B-cell lymphoma with spindle cells.Although this rare variant of primary cutaneous B-cell lymphoma is not included in the recent WHO-EORTC classification, the rarity of this tumor and its unique morphologic appearance frequently leads to misdiagnosis and delays its treatment.
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Errores Diagnósticos , Linfoma de Células B/patología , Rosácea/diagnóstico , Neoplasias Cutáneas/patología , Adulto , Biomarcadores de Tumor/análisis , Femenino , Humanos , InmunohistoquímicaRESUMEN
The discovery of BRAF mutations in 40%-60% of melanomas led to the development of BRAF inhibitors, which exhibit objective response in over 50% of patients. However, up to 98% of the patients develop at least 1 side effect. We report for the first time a patient with metastatic melanoma harboring BRAF V600E mutation that develops a primary, cutaneous small/medium CD4 T-cell lymphoma secondarily to the treatment with vemurafenib. A 54-year-old man with a history of metastatic melanoma treated with the oral BRAF inhibitor vemurafenib presents, 4 months after the initiation of the treatment, with multiple, nodular firm nonulcerated lesions on his back. Two skin biopsies from the lesions revealed a primary, cutaneous small/medium CD4 T-cell lymphoma.The extensive use of recently approved mutation-specific RAF inhibitors seems to be speeding up the emergence of unknown nonpreventable toxicities of these agents. Our patient developed a primary, cutaneous small/medium CD4 T-cell lymphoma, which presented 4 months after the commencement of vemurafenib. Although no treatment interruption is normally required, a close monitoring of the patients with advanced melanomas treated with vemurafenib seems imperative to optimize the management strategies.
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Antineoplásicos/efectos adversos , Indoles/efectos adversos , Linfoma Cutáneo de Células T/inducido químicamente , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Cutáneas/inducido químicamente , Sulfonamidas/efectos adversos , Linfocitos T CD4-Positivos/patología , Humanos , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Cutáneas/tratamiento farmacológico , VemurafenibAsunto(s)
Linfoma de Células B de la Zona Marginal/complicaciones , Linfoma Folicular/complicaciones , Mucinosis Folicular/complicaciones , Neoplasias Cutáneas/complicaciones , Anciano , Humanos , Linfoma de Células B de la Zona Marginal/patología , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Mucinosis Folicular/patología , Neoplasias Cutáneas/patologíaRESUMEN
Previous studies have demonstrated the utility of fluorescence in situ hybridization (FISH) as an ancillary method in the diagnostic workup of histopathologically ambiguous melanocytic neoplasms. A combination of probes targeting 3 loci on chromosome 6 and 1 on 11q has been reported to distinguish unequivocal melanomas and nevi with a sensitivity and specificity of 87% and 96%, respectively. However, information on how FISH should be integrated into routine clinical testing is limited. We report our experience of FISH testing of 804 ambiguous melanocytic lesions performed as part of routine workup at University of California, San Francisco. The main category (47% of all cases) for which FISH testing was requested was Spitz tumors. Other categories included the distinction of possible melanoma from combined nevi (9%), acral or mucosal nevi (9%), Clark/dysplastic nevi (7%), and blue or deep penetrating nevi (6%) and to assess the possibility of nevoid melanoma (4%). Of the ambiguous tumors successfully tested, 88% received a more definitive benign or malignant final diagnosis. Of the 630 cases that tested negative by FISH, the final diagnosis was benign in 489 (78%) cases, ambiguous in 91 cases (14%), and malignant in 50 cases (8%). A positive FISH result was observed in 124 cases, with a final diagnosis of melanoma in 117 (94%). One (1%) FISH-positive case had an equivocal final diagnosis, and 6 (5%) were interpreted, despite the positive FISH result, as melanocytic nevi. We conclude that FISH testing can help reduce the number of equivocal diagnoses in ambiguous melanocytic neoplasms, in particular if FISH testing is positive, and discuss the challenges and limitations of FISH in clinical practice.
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Cromosomas Humanos Par 11 , Cromosomas Humanos Par 6 , Hibridación Fluorescente in Situ , Melanocitos , Nevo de Células Epitelioides y Fusiformes/genética , Neoplasias Cutáneas/genética , Adolescente , Anciano , Análisis por Conglomerados , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Melanocitos/patología , Persona de Mediana Edad , Nevo de Células Epitelioides y Fusiformes/patología , Valor Predictivo de las Pruebas , Pronóstico , San Francisco , Neoplasias Cutáneas/patologíaRESUMEN
BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers, BRAF is activated by rearrangements that fuse its kinase domain to 5' partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal partners. No other mutations were identified in melanoma oncogenes. One of the seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, but not vemurafenib, could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib.