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4.
J Invest Dermatol ; 136(7): 1490-1499, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27039262

RESUMEN

Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course. The genetic etiology of the disease is poorly understood, with chromosomal abnormalities and mutations in some genes being involved in the disease. The goal of our study was to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sézary cells, 14 of them fulfilling the diagnostic criteria of Sézary syndrome. We have discovered genes that could be involved in the pathogenesis of Sézary syndrome. Some of the genes that are affected by somatic point mutations include ITPR1, ITPR2, DSC1, RIPK2, IL6, and RAG2, with some of them mutated in more than one patient. We observed several somatic copy number variations shared between patients, including deletions and duplications of large segments of chromosome 17. Genes with potential function in the T-cell receptor signaling pathway and tumorigenesis were disrupted in Sézary syndrome patients, for example, CBLB, RASA2, BCL7C, RAMP3, TBRG4, and DAD1. Furthermore, we discovered several fusion events of interest involving RASA2, NFKB2, BCR, FASN, ZEB1, TYK2, and SGMS1. Our work has implications for the development of potential therapeutic approaches for this aggressive disease.


Asunto(s)
Mutación , Síndrome de Sézary/genética , Neoplasias Cutáneas/genética , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Femenino , Eliminación de Gen , Duplicación de Gen , Humanos , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Análisis de Secuencia de ARN , Transducción de Señal
5.
J Invest Dermatol ; 135(4): 1128-1137, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25405321

RESUMEN

MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients.


Asunto(s)
Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Linfoma Cutáneo de Células T/genética , MicroARNs/metabolismo , Adulto , Anciano , Línea Celular Tumoral , Análisis por Conglomerados , Islas de CpG , Femenino , Perfilación de la Expresión Génica , Humanos , Antígeno Ki-1/metabolismo , Linfoma Cutáneo de Células T/metabolismo , Papulosis Linfomatoide/genética , Papulosis Linfomatoide/metabolismo , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/metabolismo , Masculino , Persona de Mediana Edad , Micosis Fungoide/genética , Micosis Fungoide/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas , Estudios Retrospectivos , Adulto Joven
6.
J Invest Dermatol ; 130(4): 1126-35, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19759554

RESUMEN

Mycosis fungoide (MF) patients who develop tumors or extracutaneous involvement usually have a poor prognosis with no curative therapy available so far. In the present European Organization for Research and Treatment of Cancer (EORTC) multicenter study, the genomic profile of 41 skin biopsies from tumor stage MF (MFt) was analyzed using a high-resolution oligo-array comparative genomic hybridization platform. Seventy-six percent of cases showed genomic aberrations. The most common imbalances were gains of 7q33.3q35 followed by 17q21.1, 8q24.21, 9q34qter, and 10p14 and losses of 9p21.3 followed by 9q31.2, 17p13.1, 13q14.11, 6q21.3, 10p11.22, 16q23.2, and 16q24.3. Three specific chromosomal regions, 9p21.3, 8q24.21, and 10q26qter, were defined as prognostic markers showing a significant correlation with overall survival (OS) (P=0.042, 0.017, and 0.022, respectively). Moreover, we have established two MFt genomic subgroups distinguishing a stable group (0-5 DNA aberrations) and an unstable group (>5 DNA aberrations), showing that the genomic unstable group had a shorter OS (P=0.05). We therefore conclude that specific chromosomal abnormalities, such as gains of 8q24.21 (MYC) and losses of 9p21.3 (CDKN2A, CDKN2B, and MTAP) and 10q26qter (MGMT and EBF3) may have an important role in prognosis. In addition, we describe the MFt genomic instability profile, which, to our knowledge, has not been reported earlier.


Asunto(s)
Hibridación Genómica Comparativa , Marcadores Genéticos , Pruebas Genéticas , Micosis Fungoide/genética , Micosis Fungoide/mortalidad , Biopsia , Inestabilidad Genómica , Humanos , Micosis Fungoide/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Piel/patología , Análisis de Supervivencia
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