RESUMEN
A translocation involving the cyclin-dependent kinase 6 (CDK6) gene [t(CDK6)] is a rare but recurrent abnormality in B-cell neoplasms. To further characterise this aberration, we studied 57 cases; the largest series reported to date. Fluorescence in situ hybridisation analysis confirmed the involvement of CDK6 in all cases, including t(2;7)(p11;q21) immunoglobulin kappa locus (IGK)/CDK6 (n = 51), t(7;14)(q21;q32) CDK6/immunoglobulin heavy locus (IGH) (n = 2) and the previously undescribed t(7;14)(q21;q11) CDK6/T-cell receptor alpha locus (TRA)/T-cell receptor delta locus (TRD) (n = 4). In total, 10 patients were diagnosed with chronic lymphocytic leukaemia, monoclonal B-cell lymphocytosis or small lymphocytic lymphoma, and 47 had small B-cell lymphoma (SmBL) including 36 cases of marginal zone lymphoma (MZL; 34 splenic MZLs, one nodal MZL and one bronchus-associated lymphoid tissue lymphoma). In all, 18 of the 26 cytologically reviewed cases of MZL (69%) had an atypical aspect with prolymphocytic cells. Among the 47 patients with MZL/SmBL, CD5 expression was found in 26 (55%) and the tumour protein p53 (TP53) deletion in 22 (47%). The TP53 gene was mutated in 10/30 (33%); the 7q deletion was detected in only one case, and no Notch receptor 2 (NOTCH2) mutations were found. Immunoglobulin heavy-chain variable-region (IGHV) locus sequencing revealed that none harboured an IGHV1-02*04 gene. Overall survival was 82% at 10 years and not influenced by TP53 aberration. Our present findings suggest that most t(CDK6)+ neoplasms correspond to a particular subgroup of indolent marginal zone B-cell lymphomas with distinctive features.
Asunto(s)
Antígenos CD5/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Linfoma de Células B de la Zona Marginal/metabolismo , Neoplasias del Bazo/patología , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Bronquios/diagnóstico , Neoplasias de los Bronquios/metabolismo , Diferenciación Celular , Aberraciones Cromosómicas , Femenino , Genes p53/genética , Humanos , Cadenas Pesadas de Inmunoglobulina/metabolismo , Hibridación Fluorescente in Situ/métodos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Análisis de Supervivencia , Estructuras Linfoides Terciarias/patología , Translocación Genética/genética , Trisomía/genéticaAsunto(s)
Cromosomas Humanos X/genética , Isocromosomas , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Distribución por Edad , Anciano , Médula Ósea/patología , Cromosomas Humanos X/ultraestructura , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Estudios de Seguimiento , Genes Relacionados con las Neoplasias , Humanos , Leucemia Mieloide/epidemiología , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/patología , Proteínas de Neoplasias/genética , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Proteínas Proto-Oncogénicas/genética , Distribución por SexoAsunto(s)
Variación Genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Proteína p53 Supresora de Tumor/genética , Alelos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Mutación , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Pronóstico , Análisis de Secuencia de ADNAsunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 5 , Mutación , Síndromes Mielodisplásicos/genética , Proteína p53 Supresora de Tumor/genética , Progresión de la Enfermedad , Femenino , Humanos , Lenalidomida/uso terapéutico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/diagnóstico , PronósticoRESUMEN
The PRDM16 (1p36) gene is rearranged in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) with t(1;3)(p36;q21), sharing characteristics with AML and MDS with MECOM (3q26.2) translocations. We used fluorescence in situ hybridization to study 39 haematological malignancies with translocations involving PRDM16 to assess the precise breakpoint on 1p36 and the identity of the partner locus. Reverse-transcription polymerase chain reaction (PCR) was performed in selected cases in order to confirm the partner locus. PRDM16 expression studies were performed on bone marrow samples of patients, normal controls and CD34(+) cells using TaqMan real-time quantitative PCR. PRDM16 was rearranged with the RPN1 (3q21) locus in 30 cases and with other loci in nine cases. The diagnosis was AML or MDS in most cases, except for two cases of lymphoid proliferation. We identified novel translocation partners of PRDM16, including the transcription factors ETV6 and IKZF1. Translocations involving PRDM16 lead to its overexpression irrespective of the consequence of the rearrangement (fusion gene or promoter swap). Survival data suggest that patients with AML/MDS and PRDM16 translocations have a poor prognosis despite a simple karyotype and a median age of 65 years. There seems to be an over-representation of late-onset therapy-related myeloid malignancies.
Asunto(s)
Cromosomas Humanos Par 1 , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Factores de Transcripción/genética , Translocación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Niño , Preescolar , Bandeo Cromosómico , Puntos de Rotura del Cromosoma , Femenino , Orden Génico , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Linfoma/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/mortalidad , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. DESIGN AND METHODS: We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. RESULTS: In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600 × 10(9)/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts. CONCLUSIONS: The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity.
Asunto(s)
Anemia Refractaria/patología , Anemia Sideroblástica/patología , Janus Quinasa 2/genética , Trombocitemia Esencial/patología , Trombocitosis/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Refractaria/complicaciones , Anemia Refractaria/mortalidad , Anemia Sideroblástica/complicaciones , Anemia Sideroblástica/mortalidad , Plaquetas/patología , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Recuento de Plaquetas , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/mortalidad , Trombocitosis/complicaciones , Trombocitosis/mortalidadRESUMEN
Isochromosome of the long arm of chromosome 20 with interstitial loss of material [ider(20q)] is a rare cytogenetic abnormality reported in myelodysplastic syndrome (MDS), with neither specific morphological pattern nor clear prognostic significance. The aim of this retrospective multicentric study is to compare the peripheral blood and bone marrow morphology of MDS patients with ider(20q) (n = 13) and del(20q) (n = 21) and controls (n = 47) in order to investigate whether the ider(20q) harbors specific morphological features. The secondary objective is to compare the outcome of patients from both groups. This study performed on the largest cohort of MDS patients with ider(20q) is the first that identifies specific morphological features (hypogranulated and vacuolized neutrophils and neutrophil erythrophagocytosis) allowing the identification of this cytogenetic abnormality with high sensitivity (70%) and specificity (85.7%). Suspected ider(20q) by morphology should therefore support targeted FISH tests in case of non informative karyotype. This combined approach will allow a better estimation of the prevalence of this underdiagnozed entity. The overall survival and progression-free survival did not statistically differ in both groups. However, hypogranulated and vacuolized neutrophils were significantly associated with survival.
Asunto(s)
Células Sanguíneas , Aberraciones Cromosómicas , Deleción Cromosómica , Citogenética/métodos , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Células Sanguíneas/citología , Células Sanguíneas/fisiología , Células de la Médula Ósea/citología , Células de la Médula Ósea/fisiología , Cromosomas Humanos Par 20/genética , Estudios de Cohortes , Femenino , Humanos , Hibridación Fluorescente in Situ , Isocromosomas/genética , Cariotipo , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.
Asunto(s)
Molécula 1 de Adhesión Celular/metabolismo , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Animales , Molécula 1 de Adhesión Celular/genética , Deleción Cromosómica , Cromosomas Humanos Par 11 , Femenino , Genes Supresores de Tumor , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patologíaRESUMEN
Deletion of the 17p13 chromosomal region [del(17p)] is associated with a poor outcome in multiple myeloma. Most of the studies have targeted the TP53 gene for deletion analyses, although no study showed that this gene is the deletion target. In order to address this issue, we sequenced the TP53 gene in 92 patients with multiple myeloma at diagnosis, 54 with a del(17p) and 38 lacking del(17p). At least one mutation was found in 20 patients, all of them presenting a del(17p). The analysis of the mutation location showed that virtually all of them occurred in highly conserved domains involved in the DNA-protein interactions. In conclusion, we showed that 37% of the myeloma patients with del(17p) present a TP53 mutation versus 0% in patients lacking the del(17p). The prognostic significance of these mutations remains to be evaluated.
Asunto(s)
Eliminación de Gen , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Proteína p53 Supresora de Tumor/genética , Deleción Cromosómica , Cromosomas Humanos Par 17 , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Factores de Riesgo , Síndrome de Smith-Magenis , Tasa de SupervivenciaRESUMEN
We report on a 6-years-old boy with psychomotor retardation, mild dysmorphic features and behavioral disturbances associated with epilepsy. Conventional cytogenetic analysis concluded to an interstitial de novo 6p21.2p22.3 duplication. Molecular cytogenetic analysis, including array-CGH technology, allows characterization of this 7.3Mb interstitial tandem duplication. The phenotype of this small 6p duplication reported to date is compared to other cases in the literature. Presence of epilepsy, although rare in patients with 6p duplication may be linked to genes involved in brain function and synaptic transmission in the 6p21.2p22.1 duplicated region (GABBR1, BRD2 and GRM4).
Asunto(s)
Cromosomas Humanos Par 6/genética , Discapacidades del Desarrollo/genética , Epilepsia/genética , Duplicación de Gen , Niño , Preescolar , Análisis Citogenético , Discapacidades del Desarrollo/diagnóstico , Genoma Humano , Humanos , Hibridación Fluorescente in Situ , Masculino , Análisis de Secuencia por Matrices de OligonucleótidosAsunto(s)
Puntos de Rotura del Cromosoma , Proteínas de Unión al ADN/genética , Reordenamiento Génico , Leucemia Mieloide/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas Proto-Oncogénicas/genética , Enfermedad Aguda , Adulto , Femenino , Humanos , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta , Proteínas de Fusión Oncogénica/genética , Adulto JovenRESUMEN
Many published studies have indicated that various mechanisms could be involved in the genesis of variant chronic myelogeneous leukemia (CML) translocations. These are mainly one-step or two-step mechanisms, associated or not with deletions adjacent to the translocation junction on der(9) or der(22) chromosomes (or both). Based on the mechanism of genesis, it has been suggested that the complexity may affect the occurrence of ABL1 and BCR deletions (either or both), or may be associated with the CML disease course, and thus could determine the response to imatinib therapy. Through a retrospective molecular cytogenetic study of 41 CML patients with variant Philadelphia chromosome (Ph), we explored the genesis of these variant rearrangements and analyzed the correlation with deletion status and imatinib efficiency. Our results confirmed that the one-step mechanism is the most frequent, evidenced in 30 of 41 patients (73%); 3 patients demonstrated other more complex multistep events and 8 patients (19.5%) harbored ABL1 or BCR deletions that are not significantly associated with the complexity of translocation genesis. We also found no association between one-step, two-step, or multistep mechanisms and the response to imatinib therapy.
Asunto(s)
Eliminación de Gen , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-bcr/genética , Pirimidinas/uso terapéutico , Translocación Genética , Benzamidas , Análisis Citogenético , Femenino , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Pronóstico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Estudios Retrospectivos , Tasa de SupervivenciaAsunto(s)
Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 8/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Trastornos Mieloproliferativos/genética , Translocación Genética/genética , Diagnóstico Diferencial , Femenino , Humanos , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Persona de Mediana Edad , Trastornos Mieloproliferativos/diagnósticoRESUMEN
Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (Nâ=â27) and telomeric rearrangements (Nâ=â15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (Nâ=â39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 1 , Proteínas de Unión al ADN/genética , Neoplasias Hematológicas/genética , Factores de Transcripción/genética , Línea Celular , Humanos , Hibridación Fluorescente in Situ , Polimorfismo de Nucleótido Simple , TelómeroRESUMEN
BACKGROUND: Chromosomal translocations are usually analyzed as a single entity, and are associated with a poor outcome in chronic lymphocytic leukemia. Translocations involving immunoglobulin genes are recurrent, but uncommon (<5%), and their individual prognosis is not clear. The two most frequent partners are BCL2 (18q21) and BCL3 (19q13). DESIGNS AND METHODS: Herein, 75 cases are reported of chronic lymphocytic leukemia and t(14;18) (BCL2-CLLs). Our series benefits from morphological, immunological and cytogenetical reviews. The IGHV status analyses were performed by referring laboratories. Comparison was made with our previously published series of chronic lymphocytic leukemia patients with t(14;19) (BCL3-CLLs, n=29). RESULTS: Compared with BCL3-CLLs, lymphocytosis was lower in BCL2-CLLs (p<0.008), and splenomegaly was less frequent (p<0.0001). There were more "typical" morphologies (p<0.005) and Matutes scores >4 (p<0.001) in the BCL2-CLLs group, and less CD38 expression (p<0.04). More variant BCL2-translocations were observed (t(18;22), n=11; 2t(2;18), n=2; p<0.02), and BCL2-translocation was frequently single (p<0.002). Complex karyotypes (p<0.02), trisomy 12 (p<0.03), 6q deletion (p<0.002) and TP53 deletion (p<0.02) were less frequent in BCL2-CLLs, whereas 13q deletion was more frequent (p<0.005). The IGHV gene was frequently mutated in BCL2-CLLs (p<0.0001). Treatment-free survival was longer in BCL2-CLLs (p<0.0001). CONCLUSIONS: BCL2-CLL.S express CD5 and lack expression of CD38, and have a Matutes score ≥4, frequent trisomy 12, no ATM and 6q deletions, and a mutated IGHV status. Compared to BCL3-CLLs, BCL2-CLLs are much less aggressive; indicating that identifying individual translocations and cytogenetic partners would allow improved patient stratification.