RESUMEN
BACKGROUND: Compared with sun-exposed melanomas, less is known regarding the pathogenesis of sun-protected melanomas. Sun-protected melanomas share many epidemiologic factors, but their genetic heterogeneity is not well studied. OBJECTIVE: We investigated the genomic profile of acral, mucosal, and vulvovaginal melanomas. We hypothesize that mucosal melanomas, recognized for their uniquely aggressive clinical behavior, have distinct genomic features. METHODS: We performed whole transcriptome messenger RNA and DNA (1711 genes) sequencing, messenger RNA expression profiling, tumor mutational burden, ultraviolet signature, and copy number variants analysis on 29 volar/digital acral, 7 mucosal, and 6 vulvovaginal melanomas. RESULTS: There was significant genetic heterogeneity, particularly in acral melanomas, with 36% having BRAF alterations, whereas other melanomas had none (P = .0159). Nonzero ultraviolet signatures were more frequent in acral melanomas, suggesting greater ultraviolet involvement. Mucosal melanomas formed a distinct group with increased expression of cell cycle and proliferation genes. Various targetable aberrations were identified, such as AURKA and ERBB2, in mucosal and acral melanomas, respectively. LIMITATIONS: The sample size was a small. CONCLUSION: There is significant genetic heterogeneity among sun-protected melanomas. Mucosal melanomas have upregulation in cell cycle and proliferation genes, which may explain their aggressive behavior. Ultraviolet radiation plays some role in a subset of acral but not other melanomas.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Rayos Ultravioleta/efectos adversos , Estudios Retrospectivos , Mutación , Melanoma/patología , Neoplasias Cutáneas/patología , Genómica , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) are often the earliest sign of the BAP1 tumor predisposition syndrome. Identification of BIMTs and selection of patients for germline testing affect the lives of patients with germline BAP1 mutations. OBJECTIVE: To describe the spectrum of histomorphologic findings in BAP1-inactivated melanocytic lesions to improve their recognition. We determined the frequency of sporadic versus germline cases in our cohort, assessing whether any features were statistically linked to germline status. METHODS: Histomorphologic features of BAP1-inactivated melanocytic lesions were analyzed by comparing cases with germline mutations with those with unknown or negative status. Available clinical follow-up data were reported. RESULTS: The histomorphologic spectrum of BAP1-inactivated melanocytic lesions is broad; it includes cases with spitzoid cytomorphology (69%), smaller epithelioid cells without spitzoid features (31%), and rhabdoid cytologic features (58%). BIMTs from patients with germline mutations were statistically more likely to have an extensive junctional component of BAP1-inactivated melanocytes (P = .0177). All 11 patients with suspected or confirmed germline mutations had a history of cutaneous melanoma or multiple BIMTs. LIMITATIONS: The unknown germline status of 77 patients. CONCLUSION: Approximately 12% of patients with BIMTs have germline mutations. Extensive junctional involvement in a BIMT and a personal history of melanoma or previous BIMT may be additional indications for germline testing.
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Pruebas Genéticas , Melanoma/genética , Neoplasias Primarias Múltiples/genética , Nevo Pigmentado/genética , Neoplasias Cutáneas/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética , Adulto , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Anamnesis , Melanoma/metabolismo , Melanoma/patología , Neoplasias Primarias Múltiples/metabolismo , Neoplasias Primarias Múltiples/patología , Nevo Pigmentado/metabolismo , Nevo Pigmentado/patología , Selección de Paciente , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/metabolismoRESUMEN
Recent molecular studies of spitzoid neoplasms have identified mutually exclusive kinase fusions involving ROS1, ALK, RET, BRAF, NTRK1, MET, and NTRK3 as early initiating genomic events. Pigmented spindle cell nevus (PSCN) of Reed is a morphologic variant of Spitz and may be very diagnostically challenging, having histologic features concerning for melanoma. Their occurrence in younger patients, lack of association to sun exposure, and rapid early growth phase similar to Spitz nevi suggest fusions may also play a significant role in these lesions. However, to date, there is little data in the literature focused on the molecular characterization of PSCN of Reed with next-generation sequencing. We analyzed a total of 129 melanocytic neoplasms with RNA sequencing including 67 spitzoid neoplasms (10 Spitz nevi, 44 atypical Spitz tumors, 13 spitzoid melanomas) and 23 PSCN of Reed. Although only 2 of 67 (3.0%) of spitzoid lesions had NTRK3 fusions, 13 of 23 (57%) of PSCN of Reed harbored NTRK3 fusions with 5' partners ETV6 (12p13) in 2 cases and MYO5A (15q21) in 11 cases. NTRK3 fusions were confirmed with a fluorescent in situ hybridization break-apart probe. The presence of a NTRK3 fusion correlated with younger age (P=0.021) and adnexal extension (P=0.001). Other minor fusions identified in PSCN of Reed included MYO5A-MERTK (2), MYO5A-ROS1, MYO5A-RET, and ETV6-PITX3 leading to a total of 78% with fusions. Our study suggests that the majority of PSCN of Reed are the result of genomic fusions, and the most frequent and characteristic genomic aberration is an NTRK3 fusion.
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Biomarcadores de Tumor/genética , Receptor con Dominio Discoidina 2/genética , Fusión Génica , Nevo de Células Fusiformes/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Nevo de Células Fusiformes/patología , Fenotipo , Neoplasias Cutáneas/patologíaRESUMEN
Acral melanoma is distinct from melanoma of other cutaneous sites, yet there is considerable variation within this category. To better define this variation, we assessed melanomas occurring on dorsal (n = 21), volar (n = 9), and subungual/interdigital (n = 13) acral skin as well as acral nevi (n = 24) for clinical, histologic, and molecular features. Melanomas on dorsal acral surfaces demonstrated clear differences compared with volar and subungual/interdigital melanomas. The latter two groups exhibited significantly less frequent BRAF mutations (P = 0.01), were significantly less likely to have the superficial spreading histologic subtype (P = 0.01), occurred in older patients (P = 0.05), and had more frequent involvement in non-Caucasians (P = 0.01). These differences can be explained by differing levels of UV exposure. Subungual/interdigital melanomas had the most diverse group of oncogenic mutations including PIK3CA (2/13), STK11 (2/13), EGFR (1/13), FGFR3 (1/13), and PTPN11 (1/13). In addition, subungual/interdigital melanomas had a significantly higher frequency of copy number aberrations (67%) than other subgroups (P = 0.02), particularly in CDK4 and cyclin D1, and were less likely to have BRAF mutations or a superficial spreading histologic subtype (P = 0.05) compared with volar acral melanomas. Although based on a limited sample size, differences between volar and subungual/interdigital melanomas in our study may be the result of differing levels of UV exposure.
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Melanoma/patología , Nevo/patología , Neoplasias Cutáneas/patología , Piel/patología , Luz Solar/efectos adversos , Adulto , Anciano , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Femenino , Pie/patología , Genes Supresores de Tumor , Mano/patología , Humanos , Masculino , Melanoma/etiología , Melanoma/genética , Persona de Mediana Edad , Mutación , Nevo/etiología , Nevo/genética , Oncogenes/genética , Piel/efectos de la radiación , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genéticaRESUMEN
BACKGROUND: Shiny white streaks (SWSs) are best visualized with polarized dermoscopy and correlate with dermal fibroplasia histopathologically. SWSs have been described at higher frequencies in melanomas than in benign nevi. OBJECTIVE: We assessed the diagnostic value of different patterns of SWSs and their histologic correlate in melanocytic lesions. METHODS: Polarized dermoscopic images of 1507 histopathologically diagnosed melanocytic neoplasms were analyzed for presence and pattern of SWSs. Histology was also reviewed for correlation. RESULTS: Among 1507 melanocytic neoplasms, SWSs were observed in 31 of 144 melanomas (22%) and 22 of 1363 benign neoplasms (1.6%) (P < .001). The sensitivity and specificity of SWSs for melanoma were 22% and 98%, respectively. Diffuse SWSs exhibited the greatest diagnostic value for melanoma, with sensitivity of 11.8% and specificity of 99.5%. Focal central and peripheral SWSs were comparable in diagnostic significance. The presence of SWSs was highly uncommon in dysplastic nevi, whereas in certain benign subgroups of nevi such as Spitz nevi and atypical genital special site nevi, SWSs were not uncommon. Diffuse SWSs correlated with greater breadth of deep fibroplasia than focal SWSs (P = .009), and SWSs correlated with greater Breslow depth among melanomas (P = .007). LIMITATIONS: This study was retrospective. CONCLUSION: Polarized dermoscopy is a valuable diagnostic tool in the identification of SWSs, a feature that is highly specific for melanoma.
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Dermoscopía/métodos , Melanoma/patología , Nevo Pigmentado/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Biopsia con Aguja , Estudios de Casos y Controles , Diagnóstico Diferencial , Síndrome del Nevo Displásico/diagnóstico , Síndrome del Nevo Displásico/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Melanocitos/patología , Melanoma/diagnóstico , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Nevo de Células Epitelioides y Fusiformes/diagnóstico , Nevo de Células Epitelioides y Fusiformes/patología , Nevo Pigmentado/diagnóstico , Estudios Retrospectivos , Neoplasias Cutáneas/diagnósticoAsunto(s)
Productos Biológicos/efectos adversos , Dermatitis Atópica/tratamiento farmacológico , Etanercept/efectos adversos , Infertilidad Femenina/inducido químicamente , Infertilidad Masculina/inducido químicamente , Psoriasis/tratamiento farmacológico , Adalimumab/efectos adversos , Adalimumab/uso terapéutico , Adulto , Productos Biológicos/administración & dosificación , Productos Biológicos/farmacología , Estudios de Cohortes , Dermatitis Atópica/diagnóstico , Etanercept/uso terapéutico , Femenino , Humanos , Infertilidad Femenina/epidemiología , Infertilidad Femenina/fisiopatología , Infertilidad Masculina/epidemiología , Infertilidad Masculina/fisiopatología , Masculino , Evaluación de Necesidades , Seguridad del Paciente , Psoriasis/diagnóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Given the recent National Institutes of Health proposal for balanced use of male and female cells and animals in preclinical studies, we explored whether sex bias exists in skin research. We surveyed 802 dermatological research articles from 2012 through 2013. No information about the sex of studied cells or animals was provided in 60% of papers. Among keratinocytes of known sex, 70% were male. Few studies compared male versus female cells or animals. Disclosure of sex and comparative studies contribute to our understanding of the biologic basis of sex differences. Addressing sex-speciï¬c differences in preclinical research informs subsequent clinical trial design and promotes individualized therapy.
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Investigación Biomédica , Sexismo , Piel/citología , Animales , Células Cultivadas , Cricetinae , Modelos Animales de Enfermedad , Femenino , Fibroblastos/citología , Humanos , Queratinocitos/citología , Masculino , Melanocitos/citología , Ratones , National Institutes of Health (U.S.)/normas , Conejos , Ratas , Ovinos , Porcinos , Estados Unidos , Pez CebraAsunto(s)
Etiquetado de Medicamentos/normas , Conocimientos, Actitudes y Práctica en Salud , Envejecimiento de la Piel/efectos de la radiación , Neoplasias Cutáneas/prevención & control , Quemadura Solar/prevención & control , Protectores Solares/administración & dosificación , Administración Tópica , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Piel/efectos de la radiación , Luz Solar/efectos adversos , Rayos Ultravioleta/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Zinc is the most abundant transition metal in the mammalian oocyte, and dynamic fluxes in intracellular concentration are essential for regulating both meiotic progression and fertilization. Whether the defined pathways of zinc utilization in female meiosis directly translate to mitotic cells, including the mammalian preimplantation embryo, has not been studied previously. RESULTS: We determined that zinc is the most abundant transition metal in the preimplantation embryo, with levels an order of magnitude higher than those of iron or copper. Using a zinc-specific fluorescent probe, we demonstrated that labile zinc is distributed in vesicle-like structures in the cortex of cells at all stages of preimplantation embryo development. To test the importance of zinc during this period, we induced zinc insufficiency using the heavy metal chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN). Incubation of embryos in media containing TPEN resulted in a developmental arrest that was specific to zinc chelation and associated with compromised mitotic parameters. The developmental arrest due to zinc insufficiency was associated with altered chromatin structure in the blastomere nuclei and decreased global transcription. CONCLUSIONS: These results demonstrate for the first time that the preimplantation embryo requires tight zinc regulation and homeostasis for the initial mitotic divisions of life.
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Blastocisto/metabolismo , Embrión de Mamíferos/metabolismo , Zinc/metabolismo , Animales , Blastocisto/efectos de los fármacos , Embrión de Mamíferos/efectos de los fármacos , Etilenodiaminas/farmacología , Femenino , Ratones , Microscopía Fluorescente , Mitosis/efectos de los fármacos , EmbarazoRESUMEN
Fertilization of a mammalian egg initiates a series of 'zinc sparks' that are necessary to induce the egg-to-embryo transition. Despite the importance of these zinc-efflux events little is known about their origin. To understand the molecular mechanism of the zinc spark we combined four physical approaches that resolve zinc distributions in single cells: a chemical probe for dynamic live-cell fluorescence imaging and a combination of scanning transmission electron microscopy with energy-dispersive spectroscopy, X-ray fluorescence microscopy and three-dimensional elemental tomography for high-resolution elemental mapping. We show that the zinc spark arises from a system of thousands of zinc-loaded vesicles, each of which contains, on average, 10(6) zinc atoms. These vesicles undergo dynamic movement during oocyte maturation and exocytosis at the time of fertilization. The discovery of these vesicles and the demonstration that zinc sparks originate from them provides a quantitative framework for understanding how zinc fluxes regulate cellular processes.
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Oocitos/metabolismo , Zinc/metabolismo , Animales , División del Núcleo Celular , Sondas de ADN/metabolismo , Exocitosis , Femenino , Fertilización , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Ratones , Microscopía Confocal , Microscopía Electrónica de Transmisión de Rastreo , Oocitos/ultraestructura , Zinc/químicaRESUMEN
Priapism is a known side effect of antipsychotics. The causal mechanism seems to be mediated through α1-adrenergic receptor blockade which many antipsychotics are known to possess. We present the first detailed case of iloperidone-induced priapism in a patient with bipolar disorder with psychotic features. His case highlights some of the important risk factors clinicians should consider when using iloperidone, as it may be the highest-risk antipsychotic for causing priapism given it is a very potent blocker of the alpha-adrenergic receptor.
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Antipsicóticos/efectos adversos , Trastorno Bipolar/tratamiento farmacológico , Isoxazoles/efectos adversos , Piperidinas/efectos adversos , Priapismo/inducido químicamente , Adulto , Humanos , MasculinoRESUMEN
Meiosis in mammalian females is marked by two arrest points, at prophase I and metaphase II, which must be tightly regulated in order to produce a haploid gamete at the time of fertilization. The transition metal zinc has emerged as a necessary and dynamic regulator of the establishment, maintenance, and exit from metaphase II arrest, but the roles of zinc during prophase I arrest are largely unknown. In this study, we investigate the mechanisms of zinc regulation during the first meiotic arrest. Disrupting zinc availability in the prophase I arrested oocyte by treatment with the heavy metal chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) causes meiotic resumption even in the presence of pharmacological inhibitors of meiosis. We further show that the MOS-MAPK pathway mediates zinc-dependent prophase I arrest, as the pathway prematurely activates during TPEN-induced meiotic resumption. Conversely, inhibition of the MOS-MAPK pathway maintains prophase I arrest. While prolonged zinc insufficiency ultimately results in telophase I arrest, early and transient exposure of oocytes to TPEN is sufficient to induce meiotic resumption and bypass the telophase I block, allowing the formation of developmentally competent eggs upon parthenogenetic activation. These results establish zinc as a crucial regulator of meiosis throughout the entirety of oocyte maturation, including the maintenance of and release from the first and second meiotic arrest points.
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Profase Meiótica I/fisiología , Oocitos/citología , Oocitos/metabolismo , Zinc/metabolismo , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/fisiología , Quelantes/farmacología , Etilenodiaminas/farmacología , Femenino , Técnicas In Vitro , Sistema de Señalización de MAP Quinasas , Profase Meiótica I/efectos de los fármacos , Ratones , Oocitos/efectos de los fármacos , Oogénesis/efectos de los fármacos , Oogénesis/fisiología , Partenogénesis , Inhibidores de la Síntesis de la Proteína/farmacología , Proteínas Proto-Oncogénicas c-mos/metabolismo , Telofase/efectos de los fármacos , Telofase/fisiología , Zinc/deficienciaRESUMEN
Precise coordination of meiotic progression is a critical determinant of an egg's capacity to be fertilized successfully, and zinc has emerged as a key regulatory element in this process. An early manifestation of a regulatory role for this transition metal is the significant increase in total intracellular zinc. This accumulation is essential for meiotic progression beyond telophase I and the establishment of meiotic arrest at metaphase II. The subsequent developmental event, fertilization, induces a rapid expulsion of labile zinc that is a hallmark event in meiotic resumption. In the present study, we show that the zinc fluxes work, in part, by altering the activity of the cytostatic factor (CSF), the cellular activity required for the establishment and maintenance of metaphase II arrest in the mature, unfertilized egg. We propose a model in which zinc exerts concentration-dependent regulation of meiosis through the CSF component EMI2, a zinc-binding protein. Together, the data support the conclusion that zinc itself, through its interaction with EMI2, is a central component of the CSF.
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Puntos de Control del Ciclo Celular/fisiología , Proteínas F-Box/fisiología , Meiosis/fisiología , Oocitos/citología , Proteínas Proto-Oncogénicas c-mos/fisiología , Zinc/fisiología , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Quelantes/farmacología , Etilenodiaminas/farmacología , Proteínas F-Box/efectos de los fármacos , Femenino , Meiosis/efectos de los fármacos , Ratones , Oocitos/química , Oocitos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mos/efectos de los fármacos , Zinc/deficienciaRESUMEN
Cancer therapy can be lifesaving but significantly diminish female reproductive potential. This review provides an overview of the deleterious effects of cancer treatments on reproductive function, the fertility preservation options currently available for young women, and the outcomes of pregnancy after cancer treatment. In addition, special considerations for women who are diagnosed with cancer during pregnancy are discussed. To optimize the continuum of care for the patient, new corridors of communication between obstetricians, gynecologists, and oncology specialists must be developed to ensure the best outcomes for the patient, both in terms of cancer treatment and fertility preservation.
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Continuidad de la Atención al Paciente , Preservación de la Fertilidad , Fertilidad/efectos de los fármacos , Fertilidad/efectos de la radiación , Complicaciones Neoplásicas del Embarazo/terapia , Antineoplásicos/efectos adversos , Femenino , Ginecología , Humanos , Comunicación Interdisciplinaria , Oncología Médica , Obstetricia , Embarazo , Medicina ReproductivaRESUMEN
In last few hours of maturation, the mouse oocyte takes up over twenty billion zinc atoms and arrests after the first meiotic division, until fertilization or pharmacological intervention stimulates cell cycle progression toward a new embryo. Using chemical and physical probes, we show that fertilization of the mature, zinc-enriched egg triggers the ejection of zinc into the extracellular milieu in a series of coordinated events termed zinc sparks. These events immediately follow the well-established series of calcium oscillations within the activated egg and are evolutionarily conserved in several mammalian species, including rodents and nonhuman primates. Functionally, the zinc sparks mediate a decrease in intracellular zinc content that is necessary for continued cell cycle progression, as increasing zinc levels within the activated egg results in the reestablishment of cell cycle arrest at metaphase. The mammalian egg thus uses a zinc-dependent switch mechanism to toggle between metaphase arrest and resumption of the meiotic cell cycle at the initiation of embryonic development.