RESUMEN
The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Hibridación Fluorescente in Situ , Translocación Genética , Reordenamiento Génico , Linfoma de Células B Grandes Difuso/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cromosomas Humanos Par 14/genéticaRESUMEN
Mantle cell lymphoma (MCL) is a mature B-cell neoplasm initially driven by CCND1 rearrangement with 2 molecular subtypes, conventional MCL (cMCL) and leukemic non-nodal MCL (nnMCL), that differ in their clinicobiological behavior. To identify the genetic and epigenetic alterations determining this diversity, we used whole-genome (n = 61) and exome (n = 21) sequencing (74% cMCL, 26% nnMCL) combined with transcriptome and DNA methylation profiles in the context of 5 MCL reference epigenomes. We identified that open and active chromatin at the major translocation cluster locus might facilitate the t(11;14)(q13;32), which modifies the 3-dimensional structure of the involved regions. This translocation is mainly acquired in precursor B cells mediated by recombination-activating genes in both MCL subtypes, whereas in 8% of cases the translocation occurs in mature B cells mediated by activation-induced cytidine deaminase. We identified novel recurrent MCL drivers, including CDKN1B, SAMHD1, BCOR, SYNE1, HNRNPH1, SMARCB1, and DAZAP1. Complex structural alterations emerge as a relevant early oncogenic mechanism in MCL, targeting key driver genes. Breakage-fusion-bridge cycles and translocations activated oncogenes (BMI1, MIR17HG, TERT, MYC, and MYCN), generating gene amplifications and remodeling regulatory regions. cMCL carried significant higher numbers of structural variants, copy number alterations, and driver changes than nnMCL, with exclusive alterations of ATM in cMCL, whereas TP53 and TERT alterations were slightly enriched in nnMCL. Several drivers had prognostic impact, but only TP53 and MYC aberrations added value independently of genomic complexity. An increasing genomic complexity, together with the presence of breakage-fusion-bridge cycles and high DNA methylation changes related to the proliferative cell history, defines patients with different clinical evolution.
Asunto(s)
Epigénesis Genética , Reordenamiento Génico , Linfoma de Células del Manto/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular , Ciclina D1/genética , Metilación de ADN , Femenino , Regulación Neoplásica de la Expresión Génica , Genómica , Humanos , Inmunoglobulinas/genética , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana EdadRESUMEN
Serum soluble CD23 (sCD23) levels have been acknowledged as a prognostic factor in patients with chronic lymphocytic leukemia (CLL), but their potential relevance has not been analyzed in recent times. We retrospectively studied 338 CLL, small lymphocytic lymphoma, or CLL-type monoclonal B-cell lymphocytosis patients from a single institution, with available sCD23 levels at diagnosis. Baseline features and outcomes were compared between patients with sCD23 ≤/>1000 UI/L. The 140 patients (41%) who had sCD23 > 1000 UI/L showed adverse-risk clinical and biological characteristics. High sCD23 levels were predictive of a shorter time to first treatment (5-year probability of requiring treatment: 60 vs. 20%, p < 0.0001; hazard ratio (HR) = 1.72, p = 0.003 in a multivariable model also including the CLL International Prognostic Index and the absolute lymphocyte count), and a poorer 5-year overall survival (70 vs. 82%, p = 0.0009). These data suggest the potential of sCD23 to predict treatment-free survival and to shed light on mechanisms of activity and resistance to CD23-directed therapies.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Biomarcadores de Tumor , Humanos , Recuento de Linfocitos , Modelos de Riesgos Proporcionales , Receptores de IgE , Estudios RetrospectivosRESUMEN
Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Regiones no Traducidas 3'/genética , Empalme Alternativo/genética , Linfocitos B/metabolismo , Proteínas Portadoras/genética , Cromosomas Humanos Par 9/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Proteínas de Unión al ADN , Elementos de Facilitación Genéticos/genética , Genómica , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Factor de Transcripción PAX5/biosíntesis , Factor de Transcripción PAX5/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Factores de Transcripción/genéticaRESUMEN
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and CDKN2A/ATM deletions, but the proportion with 17p/TP53 aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; P = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and TP53/CDKN2A aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions.
Asunto(s)
Biomarcadores de Tumor/genética , Leucemia/genética , Leucemia/patología , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Mutación , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Genómica , Humanos , Leucemia/clasificación , Linfoma de Células del Manto/clasificación , Masculino , Pronóstico , Tasa de SupervivenciaRESUMEN
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC-292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC-292 potently inhibited B-cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC-292 reduced tumor load and normalized tumor-associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC-292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC-292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen.
Asunto(s)
Acrilamidas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Clorhidrato de Bendamustina/farmacología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Acrilamidas/uso terapéutico , Adulto , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina/uso terapéutico , Médula Ósea/patología , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Cultivo Primario de Células , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Pirimidinas/uso terapéutico , Células Tumorales CultivadasRESUMEN
Long non-coding RNAs (lncRNAs) comprise a family of non-coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL) we performed RNA-sequencing at high depth sequencing in primary FL samples ranging from grade 1-3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNAs (dif-lncRNAs) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif-lncRNAs were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL. RP4-694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP4-694A7.2 silencing in the WSU-FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP4-694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki-67 proliferation index. In summary, lncRNAs are differentially expressed across the clinico-biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours.
Asunto(s)
Puntos de Control de la Fase G1 del Ciclo Celular , Regulación Neoplásica de la Expresión Génica , Linfoma Folicular/metabolismo , ARN Largo no Codificante/biosíntesis , ARN Neoplásico/biosíntesis , Puntos de Control de la Fase S del Ciclo Celular , Femenino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patología , Masculino , ARN Largo no Codificante/genética , ARN Neoplásico/genéticaRESUMEN
Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the in vitro response of primary cells to BRAF and ERK inhibitors. Putative damaging mutations were found in 25 of 452 patients (5.5%). Among these, BRAF was mutated in nine patients (2.0%), genes upstream of BRAF (KITLG, KIT, PTPN11, GNB1, KRAS and NRAS) were mutated in 12 patients (2.6%), and genes downstream of BRAF (MAPK2K1, MAPK2K2, and MAPK1) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydrogenase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, P=0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical features and could be pharmacologically inhibited.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Sistema de Señalización de MAP Quinasas , Mutación , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas ras/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transcriptoma , Adulto JovenRESUMEN
Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATM in 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53 mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATM mutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1 mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1 mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3 mutations in 4.2% (2% clonal, 2.2% subclonal). ATM mutations, clonal SF3B1, and both clonal and subclonal NOTCH1 mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53 and clonal NOTCH1 mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Genes p53 , Proteínas Inhibidoras de la Apoptosis/genética , Leucemia Linfocítica Crónica de Células B/genética , Proteínas de Neoplasias/genética , Fosfoproteínas/genética , Factores de Empalme de ARN/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de la Ataxia Telangiectasia Mutada/fisiología , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Células Clonales , Análisis Mutacional de ADN , Progresión de la Enfermedad , Evolución Molecular , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/fisiología , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/fisiología , Células Madre Neoplásicas , Fosfoproteínas/fisiología , Pronóstico , Factores de Empalme de ARN/fisiología , Receptor Notch1/fisiología , Tiempo de Tratamiento , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Adulto JovenRESUMEN
Diet is a modifiable risk factor for several neoplasms but evidence for chronic lymphocytic leukemia (CLL) is sparse. Previous studies examining the association between single-food items and CLL risk have yielded mixed results, while few studies have been conducted on overall diet, reporting inconclusive findings. This study aimed to evaluate the association between adherence to three dietary patterns and CLL in the multicase-control study (MCC-Spain) study. Anthropometric, sociodemographic, medical and dietary information was collected for 369 CLL cases and 1605 controls. Three validated dietary patterns, Western, Prudent and Mediterranean, were reconstructed in the MCC-Spain data. The association between adherence to each dietary pattern and CLL was assessed, overall and by Rai stage, using mixed logistic regression models adjusted for potential confounders. High adherence to a Western dietary pattern (i.e. high intake of high-fat dairy products, processed meat, refined grains, sweets, caloric drinks, and convenience food) was associated with CLL [ORQ4 vs. Q1=1.63 (95%CI 1.11; 2.39); P-trend=0.02; OR 1-SD increase=1.19 (95%CI: 1.03; 1.37)], independently of Rai stages. No differences in the association were observed according to sex, Body Mass Index, energy intake, tobacco, physical activity, working on a farm, or family history of hematologic malignancies. No associations were observed for Mediterranean and Prudent dietary patterns and CLL. This study provides the first evidence for an association between a Western dietary pattern and CLL, suggesting that a proportion of CLL cases could be prevented by modifying dietary habits. Further research, especially with a prospective design, is warranted to confirm these findings.
Asunto(s)
Dieta Mediterránea/efectos adversos , Dieta Occidental/efectos adversos , Ingestión de Energía , Leucemia Linfocítica Crónica de Células B/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , España/epidemiologíaRESUMEN
BACKGROUND: Cognitive therapy is a well-established intervention for treating elderly suffering from dementia. In particular, reality orientation and skills training seem to be effective interventions for reversing cognitive impairment among elderly, although findings are inconclusive. Therefore, a systematic update of the existing evidence of cognitive therapy for people suffering from dementia is needed. AIM: To review existing scientific evidence regarding the efficacy of cognitive therapies for elderly suffering from dementia. METHODS: Studies were retrieved from several bibliographic databases (January 2009 to December 2017) with prespecified selection criteria, data extraction, and methodological quality assessment. RESULTS: In total, 10 reality orientation, 25 skills training, and 12 mixed trials were identified as meeting the inclusion criteria and were systematically reviewed. Results from reality orientation trials showed minor effects for cognitive assessments, while skills training trials and mixed trials showed contradicting effects on cognition. Effects on other outcomes (e.g., daily functioning, depression, language) were limited or not found. CONCLUSIONS: Skills training trials and mixed trials seem to affect cognitive impairment in a positive way, although the results are inconclusive. Comparison between studies was difficult due to differences in form of intervention. Because findings are inconclusive, more structuralized and comparable randomized controlled trials are needed.
Asunto(s)
Enfermedad de Alzheimer/terapia , Terapia Cognitivo-Conductual/métodos , Adaptación Psicológica , Anciano , Enfermedad de Alzheimer/psicología , Cognición , Trastornos del Conocimiento/terapia , Trastorno Depresivo/psicología , Trastorno Depresivo/terapia , Femenino , Humanos , Lenguaje , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Prueba de Realidad , Resultado del TratamientoRESUMEN
Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes-most of which are not differentially expressed-exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences.
Asunto(s)
Linfocitos B , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Leucemia Linfocítica Crónica de Células B/genética , Anciano , Secuencia de Bases , Femenino , Perfilación de la Expresión Génica , Humanos , Región Variable de Inmunoglobulina , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Mutación , Ribosomas/genética , Empalmosomas/genéticaRESUMEN
PURPOSE: There is currently no convincing epidemiological evidence that fruit and vegetable consumption, the primary source of vitamin C, plays a role in chronic lymphocytic leukaemia (CLL) aetiology. We hypothesized that variations in vitamin C dietary intake as well as in genetic variability in vitamin C transporter gene SLC23A2 could explain some inconsistencies in the literature. METHODS: Fruit/vegetable/vitamin C consumption from food frequency questionnaires and six low-penetrance genetic susceptibility polymorphisms in vitamin C transporter gene SLC23A2 (rs1715364, rs6133175, rs1776948, rs6139587, rs369270 and rs6052937) were examined in 434 CLL cases and 1257 randomly selected controls from primary care centres with genetic data of whom 275 cases and 1094 controls having both diet and genetic information. Logistic regression models were used to estimate odds ratio (OR) and 95 % confidence intervals (CI). RESULTS: CLL patients were more likely to have a higher fruit consumption than controls (highest versus lowest quartile in g/day OR: 1.48; 95 % CI: 1.00 to 2.18; P = 0.03), whereas no associations were found with vegetable or total vitamin C intake. Based on log-additive models, rs6133175_A > G (OR: 1.19, 95 % CI: 1.00 to 1.41; P = 0.05) and rs1776948_T > A (OR: 1.20; 95 %CI: 1.01 to 1.41; P = 0.04) were associated with CLL. The haplogenotype analysis (rs1715364, rs6133175) supported the genotype results. No gene-diet interactions in CLL remained statistically significant after correction for multiple testing. CONCLUSIONS: These data suggest that both fruit intake and genetic marker in SLC23A2 may play an independent role in CLL biology.
Asunto(s)
Ácido Ascórbico/administración & dosificación , Frutas , Leucemia Linfocítica Crónica de Células B/genética , Polimorfismo de Nucleótido Simple , Transportadores de Sodio Acoplados a la Vitamina C/genética , Verduras , Anciano , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Marcadores Genéticos , Técnicas de Genotipaje , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Evaluación Nutricional , Factores de Riesgo , Factores Socioeconómicos , Encuestas y CuestionariosRESUMEN
Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.
Asunto(s)
Genoma Humano/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Secuencia de Aminoácidos , Animales , Proteínas Portadoras/genética , Análisis Mutacional de ADN , Humanos , Carioferinas/genética , Datos de Secuencia Molecular , Factor 88 de Diferenciación Mieloide/química , Factor 88 de Diferenciación Mieloide/genética , Receptor Notch1/genética , Receptores Citoplasmáticos y Nucleares/genética , Reproducibilidad de los Resultados , Proteína Exportina 1RESUMEN
Chronic lymphocytic leukemia (CLL) has few known modifiable risk factors. Recently, circadian disruption has been proposed as a potential contributor to lymphoid neoplasms' etiology. Serum melatonin levels have been found to be significantly lower in CLL subjects compared with healthy controls, and also, CLL prognosis has been related to alterations in the circadian molecular signaling. We performed the first investigation of an association between night shift work and CLL in 321 incident CLL cases and 1728 population-based controls in five areas of Spain. Participants were interviewed face-to-face by trained interviewers to collect information on sociodemographic factors, familial, medical and occupational history, including work shifts and other lifestyle factors. We used logistic regression models adjusted for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). Seventy-nine cases (25%) and 339 controls (20%) had performed night work. Overall, working in night shifts was not associated with CLL (OR = 1.06; 95% CI = 0.78-1.45, compared with day work). However, long-term night shift (>20 years) was positively associated with CLL (OR(tertile 3 vs . day-work) = 1.77; 95% = 1.14-2.74), although no linear trend was observed (P trend = 0.18). This association was observed among those with rotating (OR(tertile 3 vs . day-work) = 2.29; 95% CI = 1.33-3.92; P trend = 0.07), but not permanent night shifts (OR(tertile 3 vs . day-work) = 1.16; 95% CI = 0.60-2.25; P trend = 0.86). The association between CLL and long-term rotating night shift warrants further investigation.
Asunto(s)
Ritmo Circadiano , Leucemia Linfocítica Crónica de Células B/epidemiología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/etiología , Masculino , Melatonina/sangre , Oportunidad Relativa , Análisis de Regresión , Factores de Riesgo , España/epidemiología , Encuestas y Cuestionarios , Tolerancia al Trabajo Programado , Adulto JovenRESUMEN
We investigated CD49d (also termed ITGA4) expression and its biological and clinical correlations in 415 patients with chronic lymphocytic leukaemia. CD49d expression was stable over the course of the disease. A high expression of CD49d (>30%) was found in 142/415 (34%) patients and was associated with progressive disease (advanced clinical stage, high serum lactate dehydrogenase or ß2 -microglobulin levels; all p < 0·05) and aggressive disease biology (increased ZAP70 or CD38, unmutated IGHV, trisomy 12, mutations of NOTCH1 and SF3B1; all P < 0·05). A higher CD49d expression was also associated with a lower blood lymphocyte count and a higher number of lymphoid areas involved by the disease. Patients with high CD49d expression were treated more frequently (55% vs. 27%; P < 0·001) and earlier (median time to treatment [TTT] 65·4 months vs. not reached; P < 0·001) than those with low CD49d expression. However, no significant differences in response rates were observed. In the subgroup of patients with mutated IGHV, high CD49d expression was predictive of a shorter TTT while other markers, such as ZAP70 and CD38, were not. In conclusion, in this study CD49d expression correlated with high-risk CLL biomarkers and proved to be useful for separating patients with mutated IGHV into two different prognostic groups.
Asunto(s)
Biomarcadores de Tumor/sangre , Cadenas Pesadas de Inmunoglobulina/genética , Integrina alfa4/sangre , Leucemia Linfocítica Crónica de Células B/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Factores de TiempoRESUMEN
T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia. The primary genetic alteration in T-PLL are the inv(14)(q11q32)/t(14;14)(q11;q32) leading to TRD/TRA-TCL1A fusion, or the t(X;14)(q28;q11) associated with TRD/TRA-MTCP1 fusion. However, additional cooperating abnormalities are necessary for emergence of the full neoplastic phenotype. Though the pattern of secondary chromosomal aberrations is remarkably conserved, targets of the changes are largely unknown. We analysed a cohort of 43 well-characterized T-PLL for hotspot mutations in the genes JAK3, STAT5B and RHOA. Additionally, we selected a subset of 23 T-PLL cases for mutational screening of 54 genes known to be recurrently mutated in T-cell and other haematological neoplasms. Activating mutations in the investigated regions of the JAK3 and STAT5B genes were detected in 30% (13/43) and 21% (8/39) of the cases, respectively, and were mutually exclusive. Further, we identified mutations in the genes encoding the epigenetic regulators EZH2 in 13% (3/23), TET2 in 17% (4/23) and BCOR in 9% (2/23) of the cases. We confirmed that the JAK-STAT pathway is a major mutational target, and identified epigenetic regulators recurrently mutated in T-PLL. These findings complement the mutational spectrum of secondary aberrations in T-PLL and underscore the potential therapeutical relevance of epigenetic regulators in T-PLL.
Asunto(s)
Epigénesis Genética/genética , Janus Quinasa 3/genética , Leucemia Prolinfocítica de Células T/genética , Factor de Transcripción STAT5/genética , Anciano , Biomarcadores de Tumor/genética , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Femenino , Marcadores Genéticos/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas Proto-Oncogénicas/genética , Recurrencia , Proteínas Represoras/genética , Transducción de Señal , Proteína de Unión al GTP rhoA/genéticaRESUMEN
Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age ≤50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Factor 88 de Diferenciación Mieloide/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Transducción de Señal/genética , Adulto JovenRESUMEN
Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.