RESUMEN
Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies.
Asunto(s)
Variación Genética , Genómica , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Transducción de Señal , Adulto , Anciano , Antineoplásicos/farmacología , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN , Femenino , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Quinasas Janus/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Receptores Notch/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Thirty-three type l diabetics who used continuous subcutaneous infusion of insulin (CSll) and 24 diabetics on conventional treatment (maximum of two injections per day) were studied prospectively with ophthalmologic examinations, fundus photography, fluorescein angiography, and glycosylated hemoglobin (HbA1) determinations. Both groups were similar with respect to age, duration of diabetes, and length of follow-up. At entry almost all patients had only mild forms of diabetic retinopathy although three CSll patients had early proliferative retinopathy. The CSll groups achieved superior glycemic control throughout the study (mean HbA1 = 7.4% vs. 10.2%). After an average follow-up of more than 30 months, the CSll group showed significantly less progression of diabetic retinopathy as measured by macular aneurysm counts and by modified ETDRS grading. Careful control of glycemia may delay the progression of diabetic retinopathy.
