RESUMEN
Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.
Asunto(s)
Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Adulto , Anciano , Femenino , Genes p53 , Humanos , Leucemia Linfocítica Crónica de Células B/clasificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos ProporcionalesAsunto(s)
2',5'-Oligoadenilato Sintetasa/genética , Cromosomas Humanos Par 12/química , Intrones , Leucemia Linfocítica Crónica de Células B/genética , Polimorfismo de Nucleótido Simple , Alelos , Estudios de Casos y Controles , Mapeo Cromosómico , Frecuencia de los Genes , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Oportunidad Relativa , RiesgoRESUMEN
Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Anciano , Citogenética , Análisis Mutacional de ADN , Europa (Continente) , Femenino , Eliminación de Gen , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fosfoproteínas/genética , Polimorfismo de Nucleótido Simple , Pronóstico , Factores de Empalme de ARN , Receptor Notch1/genética , Recurrencia , Ribonucleoproteína Nuclear Pequeña U2/genética , Factores de Tiempo , Proteína p53 Supresora de Tumor/genéticaAsunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Estudios de Cohortes , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Factor 88 de Diferenciación Mieloide/genética , Fosfoproteínas/genética , Pronóstico , Factores de Empalme de ARN , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína LigasasRESUMEN
Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset #1, #2 and #8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset #2 (44%) versus subset #1 and #8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset #2 was only 8%, lower than the frequency observed in either subset #1 or #8 (19% and 14%, respectively; P=0.04 for subset #1 versus #2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy.
Asunto(s)
Biomarcadores de Tumor/genética , Proteínas Inhibidoras de la Apoptosis/genética , Leucemia Linfocítica Crónica de Células B/clasificación , Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Fosfoproteínas/genética , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Estudios de Cohortes , ADN de Neoplasias/genética , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Reacción en Cadena de la Polimerasa , Pronóstico , Factores de Empalme de ARN , Tasa de Supervivencia , Ubiquitina-Proteína LigasasRESUMEN
In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-ß and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.
Asunto(s)
Biomarcadores de Tumor/genética , Proliferación Celular , Islas de CpG/genética , Metilación de ADN , Perfilación de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Anciano , Linfocitos B/patología , Estudios de Casos y Controles , Estudios de Cohortes , ADN de Neoplasias/genética , Progresión de la Enfermedad , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , PronósticoAsunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Fosfoproteínas/genética , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , ADN/genética , Exones/genética , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Factores de Empalme de ARN , Factores de Riesgo , Países Escandinavos y Nórdicos/epidemiología , Tasa de SupervivenciaAsunto(s)
Cromosomas Humanos Par 17/genética , Eliminación de Gen , Linfoma de Células del Manto/genética , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Estudios de Cohortes , Femenino , Humanos , Linfoma de Células del Manto/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
Biological pre-treated landfill leachates of Djebel Chakir contains some macromolecular organic substances that are resistant to biological degradation. The aim of the present work is to assess the feasibility of removing refractory organic pollutants in biological pre-treated landfill leachate by solar photocatalyse process. Leachate pollutant contents are studied to assess their contribution to leachate pollution and their treatability by solar photocatalyse process. Phenol is chosen as model of pollutants, to evaluate its removal and the efficiency of the photocatalytic system. The experiments were carried out in suspended photocatalytic reactor, using TiO2 Degussa P25, under sunlight illumination (UV-A: 15-31 W/cm2). Under optimum operational conditions, applied to single reactant (phenol), the system presents a TOC removal of 90% (the degradation follows a first-order kinetic). Based on the TOC removal, the results shows that the degradation of biological pre-treated leachate follows a zero-order kinetic. After 5 h of sunlight exposure, 74% of COT is removed. The TOC removal is the best without any correction of the pH and at the TiO2 concentration of 2.5 g/L. The photocatalytic degradation of organic contaminants as well as the formation and disappearance of the by-products were followed by GC/MS. The solar photocatalysis processes induce several modifications of the matrix leading to more biodegradable forms: all the remaining and new compounds generated after the biological pre-treatment of leachate are degraded and other types of organics appear, mainly carboxylic acid, aliphatic hydrocarbons and phtalic acids.
Asunto(s)
Compuestos Orgánicos/química , Luz Solar , Álcalis , Catálisis , Concentración de Iones de Hidrógeno , Compuestos Orgánicos/metabolismo , Fotoquímica , Residuos , Contaminantes Químicos del Agua/química , Contaminantes Químicos del Agua/metabolismoRESUMEN
Heterogeneous catalytic ozonation (HCO) of wastewater is gaining both research and industrial interests. It is proved to be an advanced oxidation process since it involves hydroxyl radicals as oxidation species. Few studies have been carried out to test HCO in the treatment of landfill leachates. This work has been carried out to test three types of catalysts: activated carbon (AC), expanded perlite (EP) and titanium dioxide (TiO2) combined with ozone at 80 g/m3 gas concentration for the treatment of a leachate generated by Jebel Chakir landfill site near Tunis-capital of Tunisia. The work has shown a reduction in COD of about 45% and an increase in biodegradability (BOD5/COD) from 0.1 to 0.34. A catalyst concentration of 0.7 g/L was found optimal for the treatment of the leachate.