RESUMEN
Cytogenetic analyses (karyotype and, if necessary, appropriate complementary FISH analyses) are mandatory at diagnosis in acute lymphoblastic leukemia (ALL) as their results are taken into account in therapeutic protocols due to their diagnostic and prognostic values. In some cases, karyotype can be completed by other techniques (RT-PCR, RQ-PCR, DNA content, SNP-array, MLPA ) that can be equally or more informative than FISH. Here, we have tempted to establish guidelines concerning karyotype and FISH analyses according to the most recent data of the litterature which is reviewed here, completing the 2008 WHO classification with the recent new cytogenomic entities such as Ph-like ALL and indicating possible therapeutic implications.
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Análisis Citogenético/normas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Niño , Análisis Citogenético/métodos , Análisis Citogenético/tendencias , Hematología/organización & administración , Hematología/normas , Hematología/tendencias , Humanos , Cariotipificación/normas , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sociedades Médicas/organización & administración , Sociedades Médicas/normasRESUMEN
The prognostic interest of cytogenetic remission and fluorescent in situ hybridization (FISH) evaluation in patients with abnormal karyotype acute myeloid leukemia (AML) has been poorly studied. Among 198 patients that reached complete remission (CR), 24 did not reach cytogenetic remission (CyCR). CyCR had no prognosis impact, especially in patients with intermediate or unfavorable cytogenetic. Twenty of 52 evaluated patients in CyCR did not reach FISH CR. FISH CR was associated with better OS (p=0.004) and tended to be associated with better disease-free survival (DFS) (p=0.08). FISH evaluation may be a useful tool for prognosis evaluation and minimal residual disease (MRD) assessment in patients with abnormal cytogenetic AML.
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Análisis Citogenético/métodos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Cariotipo Anormal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasia Residual , Valor Predictivo de las Pruebas , Pronóstico , Inducción de Remisión , Adulto JovenRESUMEN
Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Cromosomas Humanos Par 6 , Cromosomas Humanos Par 9 , Leucemia Mieloide/genética , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Oncogénicas/genética , Translocación Genética , Adolescente , Médula Ósea/patología , Niño , Preescolar , Femenino , Perfilación de la Expresión Génica , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Recién Nacido , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/mortalidad , Leucemia Mieloide/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Proteínas de Unión a Poli-ADP-Ribosa , Recurrencia , Resultado del TratamientoRESUMEN
Germline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small â¼0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression.
Asunto(s)
Eliminación de Gen , Leucemia Mieloide Aguda/genética , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Anciano , Alelos , Hibridación Genómica Comparativa , Femenino , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Persona de Mediana Edad , Tasa de Mutación , Neurofibromina 1/deficiencia , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications. DESIGN AND METHODS: One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20 × 10(9)/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant. RESULTS: Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%-38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. CONCLUSIONS Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value.
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Enfermedades de la Médula Ósea/complicaciones , Insuficiencia Pancreática Exocrina/complicaciones , Enfermedades Hematológicas/clasificación , Enfermedades Hematológicas/etiología , Lipomatosis/complicaciones , Enfermedades de la Médula Ósea/mortalidad , Insuficiencia Pancreática Exocrina/mortalidad , Femenino , Estudios de Seguimiento , Francia , Enfermedades Hematológicas/mortalidad , Humanos , Lactante , Lipomatosis/mortalidad , Masculino , Pronóstico , Estudios Prospectivos , Sistema de Registros , Factores de Riesgo , Síndrome de Shwachman-Diamond , Tasa de SupervivenciaRESUMEN
We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Reordenamiento Génico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Niño , Preescolar , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 8 , Estudios de Cohortes , Análisis Citogenético , Femenino , Estudios de Asociación Genética , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Translocación Genética , TrisomíaRESUMEN
PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.
Asunto(s)
Análisis Citogenético , Mutación/genética , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Puntos de Rotura del Cromosoma , Cromosomas Humanos Par 9/genética , Clonación Molecular , Estudios de Cohortes , Femenino , Francia , Regulación Leucémica de la Expresión Génica , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Adulto JovenRESUMEN
BACKGROUND: Anemia is a characteristic of myelodysplastic syndromes, such as the rare 5q- syndrome, but its mechanism remains unclear. In particular, data are lacking on the terminal phase of differentiation of erythroid cells (enucleation) in myelodysplastic syndromes. DESIGN AND METHODS: We used a previously published culture model to generate mature red blood cells in vitro from human hematopoietic progenitor cells in order to study the pathophysiology of the 5q- syndrome. Our model enables analysis of cell proliferation and differentiation at a single cell level and determination of the enucleation capacity of erythroid precursors. RESULTS: The erythroid commitment of 5q(del) clones was not altered and their terminal differentiation capacity was preserved since they achieved final erythroid maturation (enucleation stage). The drop in red blood cell production was secondary to the decrease in the erythroid progenitor cell pool and to impaired proliferative capacity. RPS14 gene haploinsufficiency was related to defective erythroid proliferation but not to differentiation capacity. CONCLUSIONS: The 5q- syndrome should be considered a quantitative rather than qualitative bone marrow defect. This observation might open the way to new therapeutic concepts.
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Células de la Médula Ósea/citología , Diferenciación Celular/genética , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Eritrocitos/citología , Células Precursoras Eritroides/fisiología , Síndromes Mielodisplásicos/genética , Anciano , Anciano de 80 o más Años , Células Cultivadas , Eritropoyesis , Femenino , Humanos , Masculino , Síndromes Mielodisplásicos/patología , Proteínas Ribosómicas/genéticaRESUMEN
Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitt's lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs<2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs >2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04-71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 <89.58-96.81> MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 <60.96-61> MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 <60.43-60.53> that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies.
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Linfoma de Burkitt/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Línea Celular Tumoral , Aberraciones Cromosómicas , Citogenética , Progresión de la Enfermedad , Humanos , Inmunoglobulinas/metabolismo , Hibridación Fluorescente in Situ , Cariotipificación , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Oligonucleótidos/química , Resultado del TratamientoAsunto(s)
Genes ras , Cardiopatías Congénitas/genética , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Leucemia Monocítica Aguda/genética , Proteínas de la Membrana/deficiencia , Síndromes Neurocutáneos/genética , Proteínas Adaptadoras Transductoras de Señales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apendicitis/complicaciones , Transformación Celular Neoplásica/genética , Predisposición Genética a la Enfermedad , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/fisiología , Leucemia Monocítica Aguda/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Infecciones por Pseudomonas/complicaciones , Inducción de Remisión , Sepsis/complicacionesRESUMEN
Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.
Asunto(s)
Cromosomas Humanos Par 11/genética , Reordenamiento Génico , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Translocación Genética , Niño , Mapeo Cromosómico , Cromosomas Humanos Par 9/genética , Supervivencia sin Enfermedad , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , Agencias Internacionales , Cariotipificación , Pronóstico , Estudios RetrospectivosRESUMEN
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 SupervivenciaRESUMEN
PURPOSE: To determine whether minimal residual disease (MRD) measured by Wilms' tumor gene 1 (WT1) expression is a prognostic marker in pediatric acute myeloid leukemia (AML), we quantified WT1 transcript by real-time quantitative-polymerase chain reaction in 92 AML at diagnosis and during follow-up. PATIENTS AND METHODS: Patients (median age, 6 years; cytogenetics, favorable 27%, intermediate 59%, poor 13%) were treated between 1995 and 2002 and enrolled in Leucémie aiguë Myéloblastique Enfant (LAME) 89/91, LAME 99 pilot study and Acute Promyelocytic Leukemia French collaborative protocols. With a median follow-up of 26 months, event-free survival was 56% with a standard deviation (SD) of 5% and overall survival of 62.5% with an SD of 6%. WT1 copy number was normalized by TATA box binding protein gene transcripts and expressed as WT1/TBP x 1,000 ratio. Median WT1 ratio in normal patient controls was 12 (range, 0 to 57). A level over two SD than normal bone marrow controls (ie, WT1 ratio > 50), was considered as significant overexpression. RESULTS: At diagnosis, WT1 overexpression was detected in 78% of patients (72 of 92 patients; median copy ratio, 2231). The WT1 values were significantly higher (P = .01) in favorable cytogenetics and lower (P < .0001) in M5-FAB subtype, 11q23 rearrangements (P < .001), and infants (P = .003) and demonstrate a strong correlation with fusion transcript AML1-ETO, PML-RARalpha expression. After induction treatment, WT1 ratio was analyzed in 46 of 72 patients and found above 50 in nine of 36 patients and five of 25 patients at D35-50 and 3 to 5 months, respectively. WT1 ratio > 50 after induction is an independent prognostic risk factor of relapse (P = .002) and death (P = .02). CONCLUSION: WT1 quantification is an informative molecular marker for MRD in pediatric AML and is now performed as prospective analysis in ELAM02 protocol.
Asunto(s)
Genes del Tumor de Wilms , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Niño , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Dosificación de Gen , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Análisis Multivariante , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , ARN Mensajero/análisis , Proteína 1 Compañera de Translocación de RUNX1 , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Chromosome 21 is frequently rearranged in hematopoietic malignancies. In order to detect new chromosomal aberrations, the Groupe Français de Cytogénétique Hématologique collected a series of 107 patients with various hematologic disorders and acquired structural abnormalities of the long arm of chromosome 21. The abnormalities were subclassified into 10 groups, according to the location of the 21q breakpoint and the type of abnormality. Band 21q22 was implicated in 72 patients (excluding duplications, triplications, and amplifications). The involvement of the RUNX1 gene was confirmed in 10 novel translocations, but the gene partners were not identified. Eleven novel translocations rearranging band 21q22 with bands 1q25, 2p21, 2q37, 3p21, 3p23, 4q31, 6p24 approximately p25, 6p12, 7p15, 16p11, and 18q21 were detected. Rearrangements of band 21q11 and 21q21 were detected in six novel translocations with 5p15, 6p21, 15q21, 16p13, and 20q11 and with 1p33, 3q27, 5p14, 11q11, and 14q11, respectively. Duplications, triplications, amplifications, and isodicentric chromosomes were detected in eight, three, eight, and three patients, respectively. The present study shows both the wide distribution of the breakpoints on the long arm of chromosome 21 in hematopoietic malignancy and the diversity of the chromosomal rearrangements and the hematologic disorders involved. The findings invite further investigation of the 21q abnormalities to detect their associated molecular rearrangements.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 21/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Enfermedades Hematológicas/genética , Translocación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Conducta Cooperativa , Femenino , Francia/epidemiología , Enfermedades Hematológicas/epidemiología , Enfermedades Hematológicas/patología , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Estudios RetrospectivosAsunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 8 , Diploidia , Sarcoma de Ewing/genética , Translocación Genética , Adolescente , Terapia Combinada , Resultado Fatal , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/cirugíaRESUMEN
Comparative genomic hybridization to bacterial artificial chromosome (BAC)-arrays (array-CGH) is a highly efficient technique, allowing the simultaneous measurement of genomic DNA copy number at hundreds or thousands of loci, and the reliable detection of local one-copy-level variations. We report a genome-wide amplification method allowing the same measurement sensitivity, using 1 ng of starting genomic DNA, instead of the classical 1 microg usually necessary. Using a discrete series of DNA fragments, we defined the parameters adapted to the most faithful ligation-mediated PCR amplification and the limits of the technique. The optimized protocol allows a 3000-fold DNA amplification, retaining the quantitative characteristics of the initial genome. Validation of the amplification procedure, using DNA from 10 tumour cell lines hybridized to BAC-arrays of 1500 spots, showed almost perfectly superimposed ratios for the non-amplified and amplified DNAs. Correlation coefficients of 0.96 and 0.99 were observed for regions of low-copy-level variations and all regions, respectively (including in vivo amplified oncogenes). Finally, labelling DNA using two nucleotides bearing the same fluorophore led to a significant increase in reproducibility and to the correct detection of one-copy gain or loss in >90% of the analysed data, even for pseudotriploid tumour genomes.
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Cromosomas Artificiales Bacterianos , ADN/análisis , Genómica/métodos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Línea Celular Tumoral , ADN de Neoplasias/análisis , Genoma Humano , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
To reveal the relationship between hypodiploidy with 30 to 39 chromosomes and near-triploidy in acute lymphoblastic leukemia (ALL), we studied 24 patients presenting with one of these aneuploidies among 623 adults with ALL registered in the Leucemie Aigue Lymphoblastique de l'Adulte (LALA) protocols. The 2 ploidy groups presented a striking similarity of their cytogenetic profiles: chromosomes 2, 3, 4, 7, 13, 15, 16, and 17, significantly monosomic in hypodiploidy 30 to 39, were also frequently disomic in near-triploidy, whereas those retained in pairs in hypodiploidy 30 to 39 were frequently tetrasomic in near-triploidy. DNA content data revealed the simultaneous presence of 2 aneuploid peaks in most tested cases (DNA indexes: 0.72-0.87/1.39-1.89) and a multiple correspondence analysis applied on cytogenetic profiles ascertained their strong relationship. We thus assumed that near-triploidy derives from the duplication of hypodiploidy with 30 to 39 chromosomes and that both aneuploid groups are 2 expressions of the same disease. These 24 patients presented with B-cell phenotype, low leukocytoses (median white blood cell count, 4.2 x 10(9)/L), and poor prognosis (complete remission, 57%; median disease-free-survival, 8 months; median survival, 10.4 months) comparable to that of Ph(+) patients treated according to the same protocol. We suggest that hypodiploidy with 30 to 39 chromosomes or near-triploidy should be regarded as a new high-risk factor in the risk stratification of adult ALL protocols.
Asunto(s)
Cromosomas Humanos/genética , Diploidia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Anciano , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Cariotipificación , Masculino , Persona de Mediana Edad , Poliploidía , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Pronóstico , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Two cases of renal cell carcinoma (RCC) carrying a t(X;1)(p11.2;q21) in a 12-year-old boy and a 14 year-old girl, two cases with a t(X;1)(p11.2;p34) in a 9-year-old boy and a 31-year-old woman, and one case with a t(X;17)(p11.2;q25) in a 15-year-old boy are reported. Two are likely papillary RCC, with clear or slightly eosinophilic cells, and two to a clear cell RCC; one shows a mixture of papillary and clear cell RCC architecture. Renal cell carcinomas with translocations involving Xp11.2 form a specific entity characterized by subtle pathologic features and younger age of occurrence, especially for those with the t(X;17).
Asunto(s)
Carcinoma de Células Renales/genética , Cromosomas Humanos X/genética , Translocación Genética/genética , Adolescente , Adulto , Carcinoma de Células Renales/patología , Niño , Femenino , Humanos , Cariotipificación , MasculinoRESUMEN
Various genomic alterations have been detected in glioblastoma. Chromosome 7p, with the epidermal growth factor receptor locus, together with chromosome 10q, with the phosphatase and tensin homologue deleted in chromosome 10 and deleted in malignant brain tumors-1 loci, and chromosome 9p, with the cyclin-dependent kinase inhibitor 2A locus, are among the most frequently damaged chromosomal regions in glioblastoma. In this study, we evaluated the genetic status of 32 glioblastomas by comparative genomic hybridization; the sensitivity of comparative genomic hybridization versus differential polymerase chain reaction to detect deletions at the phosphatase and tensin homologue deleted in chromosome 10, deleted in malignant brain tumors-1, and cyclin-dependent kinase inhibitor 2A loci and amplifications at the cyclin-dependent kinase 4 locus; the frequency of genetic lesions (gain or loss) at 16 different selected loci (including oncogenes, tumor-suppressor genes, and proliferation markers) mapping on 13 different chromosomes; and the possible existence of a statistical association between any pair of molecular markers studied, to subdivide the glioblastoma entity molecularly. Comparative genomic hybridization showed that the most frequent region of gain was chromosome 7p, whereas the most frequent losses occurred on chromosomes 10q and 13q. The only statistically significant association was found for 7p gain and 10q loss.
Asunto(s)
Neoplasias Encefálicas/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 7 , Glioblastoma/genética , Humanos , Hibridación de Ácido Nucleico , Reacción en Cadena de la PolimerasaRESUMEN
De novo erythroleukemia (EL) is a rare disease. Reported median survival are poor and vary from 4 to 14 months. The value of hematopoietic stem cell transplantation (HSCT) for EL is unknown. This EBMT registry study reports on the largest series of patients with EL treated with HSCT in first complete remission-103 autologous and 104 HLA identical sibling allogeneic HSCT. Outcome and identification of prognostic factors for each type of transplantation were evaluated. For autologous HSCT, outcome at 5 years showed a leukemia-free survival (LFS) of 26% +/- 5%, a relapse incidence (RI) of 70% +/- 6%, and a transplant-related mortality (TRM) of 13% +/- 4%. By multivariate analysis, the only prognostic factor was age. For allogeneic HSCT, outcome at 5 years showed an LFS of 57% +/- 5%, an RI of 21% +/- 5%, and a TRM of 27% +/- 5%. By multivariate analysis, prognostic factors were graft-versus-host disease and age. This study represents the largest series of de novo EL treated with HSCT and shows that allogeneic HSCT is by far the most effective treatment.