Asunto(s)
Dermatitis/epidemiología , Leucemia Linfocítica Crónica de Células B/patología , Neoplasias Cutáneas/epidemiología , Piel/patología , Anciano , Anciano de 80 o más Años , Comorbilidad , Dermatitis/genética , Dermatitis/patología , Progresión de la Enfermedad , Femenino , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Factores de Riesgo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n=211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P<0.001) and VH usage (P<0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P<0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P<0.001) along with Binet stage (P<0.001). These findings were corroborated in a validation series (n=97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.
Asunto(s)
Linfocitos B/metabolismo , Biomarcadores de Tumor/genética , Epigénesis Genética , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Linfocitos B/clasificación , Linfocitos B/patología , Metilación de ADN , Progresión de la Enfermedad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , 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 Proporcionales , Máquina de Vectores de Soporte , Análisis de Supervivencia , Tiempo de Tratamiento , Resultado del TratamientoAsunto(s)
Linfoma de Burkitt/genética , Metilación de ADN , Herpesvirus Humano 4 , Secuenciación de Nucleótidos de Alto Rendimiento , Linfoma de Burkitt/virología , Línea Celular Tumoral , Exoma , Regulación Neoplásica de la Expresión Génica , Herpesvirus Humano 4/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Cariotipificación , Polimorfismo de Nucleótido SimpleRESUMEN
We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 17 , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Hibridación Fluorescente in Situ , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Pronóstico , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Trasplante Homólogo , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
The recently discovered MLT/MALT1 gene is fused with the API2 gene in the t(11;18)(q21;q21), which characterizes about one-third of MALT lymphomas. In order to screen for variant translocations and amplifications of MLT/MALT1, we have developed a novel, undirected two-color interphase fluorescence in situ hybridization (FISH) assay with two PAC clones flanking MLT/MALT1. This assay was applied to 108 marginal zone B-cell lymphomas (MZBCLs), including 72 extranodal MALT lymphomas, 17 nodal, and 19 splenic MZBCL. In 19 MALT lymphomas (26%), but in none of the nodal or splenic MZBCL, separated hybridization signals of the MLT/MALT1 flanking probes, were found. Further FISH analyses showed that 12 of these 19 cases displayed the classical t(11;18) and the remaining seven cases revealed the novel t(14;18)(q32;q21), involving the MLT/MALT1 and IGH genes. The frequency at which these translocations occurred varied significantly with the primary location of disease. The t(11;18) was mainly detected in gastrointestinal MALT lymphomas, whereas the t(14;18) occurred in MALT lymphomas of the parotid gland and the conjunctiva. Amplification of MLT/MALT1 was not observed in any of the lymphomas analyzed. We conclude that the translocations t(11;18)(q21;q21) and t(14;18)(q21;q32) represent the main structural aberrations involving MLT/MALT1 in MALT lymphomas, whereas true amplifications of MLT/MALT1 occur rarely in MZBCL.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Linfoma de Células B de la Zona Marginal/genética , Proteínas de Neoplasias/genética , Proteínas/genética , Translocación Genética , Neoplasias de la Mama/patología , Caspasas , Mapeo Cromosómico , Neoplasias Gastrointestinales/genética , Humanos , Hibridación Fluorescente in Situ , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Neoplasias de la Parótida/genética , Estudios Retrospectivos , Neoplasias Gástricas/genéticaAsunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 18/genética , Neoplasias Pulmonares/genética , Linfoma de Células B de la Zona Marginal/genética , Translocación Genética , Cartilla de ADN/química , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
In contrast to other subtypes of lymphoproliferative malignancies, the genetic mechanisms underlying the pathogenesis of hairy cell leukemia (HCL) are unknown. We studied densely infiltrated splenic tissue of 14 cases of HCL for the presence of chromosomal gains and losses by comparative genomic hybridization (CGH). Chromosomal imbalances were detected in only four of the 14 cases. Chromosomal gains involved the regions 5q13-q31 (two cases) and 1p32-p36.2 (one case). A loss of the region 11q14-q22 was found in one additional patient. The imbalances affecting the regions 5q and 11q were confirmed by interphase fluorescence in situ hybridization (FISH) using PAC clone 144G9 (5q31) and YAC clones 755B11 (11q22.3-q23.1) and 801E11 (11q22.3-q23.1 spanning the ATM gene) and occurred in 61% to 75% of analyzed nuclei. The latter DNA probes and probes hybridizing to chromosomal regions, which are frequently deleted in other subtypes of non-Hodgkin lymphomas (NHL), namely 9p21/ P16(INK4A), 13q14/D13S25, and 17p13/P53 were subsequently applied to all 14 cases of HCL, but no additional abnormalities were found. We conclude that overrepresentation of chromosome 5 represents a recurrent aberration in HCL and that the commonly overrepresented region resides in 5q13-q31. Chromosomal imbalances including deletions of the tumor suppressor gene loci 9p21/P16(INK4A), 13q14/D13S25, and 17p13/P53 rarely occur in HCL in contrast to some other subtypes of B-cell NHL. The pathogenetic role of 11q/ATM alterations in HCL remains to be determined.
