RESUMEN
BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , Neoplasias/genética , Nevo/genética , Neoplasias Cutáneas/genética , Simportadores/genética , Adulto , Anciano , Anhidrasa Carbónica IX/genética , Anhidrasa Carbónica IX/metabolismo , Estudios de Casos y Controles , Metabolismo Energético/genética , Femenino , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Melanoma/diagnóstico , Melanoma/mortalidad , Melanoma/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Neoplasias/diagnóstico , Neoplasias/mortalidad , Neoplasias/patología , Nevo/diagnóstico , Nevo/mortalidad , Nevo/patología , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Transducción de Señal , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Simportadores/metabolismoRESUMEN
Acral lentiginous melanoma (ALM) is the less common subtype with singular characterization. TERT (human telomerase reverse transcriptase) promoter mutations have being described as recurrent in melanomas and infrequent in ALM, but their real incidence and clinical relevance is unclear. The objectives of this study were to describe the prevalence of TERT promoter mutations in ALM, and correlate with the molecular profile of other drive genes and clinical features. Sixty-one samples from 48 patients with ALM were analyzed. After DNA isolation, the mutation profiles of the hotspot region of BRAF, NRAS, KIT, PDGFRA, and TERT genes were determined by PCR amplification followed by direct Sanger sequencing. KIT, PDGFRA, and VEGFR2 gene amplification was performed by quantitative PCR. Clinical information such as survival, clinical stage, and Breslow tumor classification were obtained from medical records. TERT promoter mutations were found in 9.3% of the cases, BRAF in 10.3%, NRAS in 7.5%, KIT in 20.7%, and PDGFRA in 14.8% of ALM. None of the cases showed KIT, PDGFRA, or VEGFR2 gene amplification. We found an association between KIT mutations and advanced Clark level (IV and V, P=0.043) and TERT promoter mutations with low mitotic index. No other significant associations were observed between mutation profile and patients' clinical features nor survival rates. Oncogenic TERT promoter mutations are present in a fraction of ALMs. No relevant associations were found between TERT mutation status and clinical/molecular features nor survival. Mutations of KIT and PDGFRA are the most common genetic alterations, and they can be therapeutic targets for these patients.