RESUMEN
This study piloted a pan-solid-tumor next generation sequence (NGS)-based laboratory developed test as a diagnostic aid in melanocytic tumors. 31 cases (4 "epithelioid" nevi, 5 blue nevi variants, 7 Spitz tumors [3 benign and 4 malignant] and 15 melanomas) were evaluated. All tumors [median diameter 7 mm (range 4-15 mm); median thickness 2.25 mm (range 0.25-12 mm)] yielded satisfactory results. The number of small nucleotide variants/tumor was significantly different between melanoma (median 18/tumor, range 4-71) and all other lesions (median 8/tumor, range 3-17) (P < 0.004) and malignant (median 16/tumor, range 4-71) vs benign lesions (median 7/tumor, range 3-14) (P = 0.01). BRAF, MET, NTRK1, and ROS fusions only occurred in benign Spitz tumors; EML4 fusion, BRAF, MAP2K1 and TERT mutations occurred in malignant Spitz tumors and/or melanoma. Amplifications and NRAS and NF1 mutations only occurred in melanoma. Most melanomas contained >1 pathogenic alteration. Developed NGS-based criteria correctly classified all malignant lesions in this series. 10/12 cases showed concordance with FISH; consensus diagnosis agreed with NGS classification in FISH-non-concordant cases. This pilot study suggests that NGS may be an effective diagnostic adjunct comparable to FISH, but further studies with larger numbers of cases are needed.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/clasificación , Melanocitos/metabolismo , Melanocitos/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Consenso , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Hibridación Fluorescente in Situ/métodos , Hibridación Fluorescente in Situ/estadística & datos numéricos , Lactante , Masculino , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Nevo Azul/genética , Nevo Azul/patología , Nevo de Células Epitelioides y Fusiformes/genética , Nevo de Células Epitelioides y Fusiformes/patología , Nucleótidos/genética , Proyectos Piloto , Carga Tumoral/genética , Adulto JovenRESUMEN
Resveratrol (RES) is a potent anti-cancer agent. We have previously reported that RES arrests the growth of invasive human A431 squamous cell carcinoma (SCC) cells. In this study, we show that oral administration of RES to highly tumor-susceptible p53(+/-)/SKH-1 mice markedly delayed UV-induced skin tumorigenesis and reduced the malignant conversion of benign papillomas to SCCs. Transforming growth factor-ß2 (TGF-ß2) was predominantly overexpressed in UV-induced SCCs and its expression was diminished in RES-treated SCCs/skin. In addition to the inhibition of TGF-ß2 expression, RES increased the level of epithelial cadherin. This RES-mediated TGF-ß2 downregulation led to the inhibition of both TGF-ß2/Smad-dependent and -independent pathways, and suppressed the invasiveness of A431 cells. Addition of TGF-ß2, but not TGF-ß1, rescued the RES-mediated downregulation of p-extracellular signal-regulated kinases 1/2, p-Smad3, and α-smooth muscle actin. The protein kinase B (Akt) substrate cAMP response-binding protein (pCREB) transcription factor is known to regulate TGF-ß2 expression, and RES treatment decreased phosphorylation of Akt and pCREB. Expression of constitutively active Akt blocked RES inhibition of CREB and TGF-ß2, and rescued RES inhibition of cellular invasiveness. Our data indicate that RES suppresses UV-induced malignant tumor progression in p53(+/-)/SKH-1 mice and that RES-inhibited invasiveness of human A431 SCC cells appears to occur, in part, through the Akt-mediated downregulation of TGF-ß2.