RESUMEN
We previously showed that complex karyotypes (CK) and chromosome 13q abnormalities have an adverse prognostic impact in childhood Burkitt lymphomas/leukemias (BL) and diffuse large B-cell lymphomas (DLBCL). The aim of our study was to identify recurrent alterations associated with MYC rearrangements in aggressive B-cell lymphomas with CK. Multicolor fluorescence in situ hybridization (M-FISH) was performed in 84 patient samples (59 adults and 25 children), including 37 BL (13 lymphomas and 24 acute leukemias), 12 DLBCL, 28 B-cell lymphomas with intermediate features (DLBCL/BL), 4 B-cell precursor acute lymphoblastic leukemias (BCP-ALL), and 3 unclassifiable B-cell lymphomas. New (cytogenetically undetected) abnormalities were identified in 80% of patients. We also refined one-third of the chromosomal aberrations detected by karyotyping. M-FISH proved to be more useful in identifying chromosomal partners involved in unbalanced translocations and in revealing greater complexity of 13q rearrangements. Most of the newly identified or refined recurrent alterations involved 1q, 13q and 3q (gains/losses), 7q and 18q (gains), or 6q (losses), suggesting that these secondary aberrations may play a role in lymphomagenesis. Several patterns of genomic aberrations were identified: 1q gains in BL, trisomies 7 in DLBCL, and 18q-translocations in adult non-BL. BCP-ALL usually displayed an 18q21 rearrangement. BL karyotypes were less complex and aneuploid than those of other MYC-rearranged lymphomas. BCP-ALL and DLBCL/BL were associated with a higher rate of early death than BL and DLBCL. These findings support the categorization of DLBCL/BL as a distinct entity and suggest that BL with CK are indeed different from other aggressive MYC-rearranged lymphomas, which usually show greater genetic complexity. © 2012 Wiley Periodicals, Inc.
Asunto(s)
Linfoma de Burkitt/genética , Aberraciones Cromosómicas , Cromosomas Humanos , Reordenamiento Génico , Genes myc , Linfoma de Células B/genética , Cariotipo Anormal , Adolescente , Niño , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , MasculinoAsunto(s)
Proteínas de Ciclo Celular/genética , Fusión Génica , Janus Quinasa 2/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Inversión de Secuencia , Trombocitemia Esencial/genética , Anciano de 80 o más Años , Sustitución de Aminoácidos/fisiología , Secuencia de Bases , Crisis Blástica/patología , Fusión Génica/fisiología , N-Metiltransferasa de Histona-Lisina , Humanos , Masculino , Proteínas Nucleares , Fenilalanina/genética , Polimorfismo de Nucleótido Simple/fisiología , Proteínas de Unión al ARN , Inversión de Secuencia/fisiología , Trombocitemia Esencial/patología , Valina/genéticaRESUMEN
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 , TelómeroAsunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 19 , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Miosina Tipo I/genética , Translocación Genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 19/genética , Frecuencia de los Genes , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Proteínas de Fusión Oncogénica/genética , Recurrencia , Translocación Genética/fisiologíaAsunto(s)
Cromosomas Humanos Par 1/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas c-abl/genética , Precursores del ARN/genética , Proteínas de Unión al ARN/genética , Adulto , Cromosomas Humanos Par 9/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Factor de Empalme Asociado a PTB , ARN Mensajero/genética , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenAsunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 22/genética , Variación Genética/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/etiología , Proteínas de Fusión Oncogénica/genética , Translocación Genética/genética , Anciano , Proteína p300 Asociada a E1A/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/patología , Masculino , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Proteína de la Leucemia Mieloide-Linfoide/genéticaRESUMEN
We performed a multicentric study to assess the impact of two different culture procedures on the detection of chromosomal abnormalities in 217 consecutive unselected cases with chronic lymphocytic leukemia (CLL) referred for routine analysis either at the time of diagnosis (n = 172) or during disease evolution (n = 45). Parallel cultures of peripheral blood or bone marrow were set up with the addition of either the conventional B-cell mitogen 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or a combination of CpG oligonucleotide (CpG) and interleukin-2 (IL-2). Cytogenetic analyses were performed on both cultures. Clonal abnormalities were identified in 116 cases (53%). In 78 cases (36%), the aberrant clone was detected in both cultures. Among these, the percentages of aberrant metaphases were similar in both conditions in 17 cases, higher in the CpG/IL-2 culture in 43 cases, and higher in the TPA culture in 18 cases. Clonal aberrations were detected in only one culture, either in CpG/IL-2 or TPA in 33 (15%) and 5 (2%) cases, respectively. Taken together, abnormal karyotypes were observed in 51% with CpG/IL-2 and 38% with TPA (P < 0.0001). Application of FISH (n = 201) allowed the detection of abnormalities not visible by conventional cytogenetic analysis in 80 cases: del(13q) (n = 71), del(11q) (n = 5), +12 (n = 2), del(14q) (n = 1), and del(17p) (n = 1). In conclusion, our results confirm that CpG/IL-2 stimulation increases the detection rate of chromosomal abnormalities in CLL compared with TPA and that further improvement can be obtained by FISH. However, neither conventional cytogenetics nor FISH detected all aberrations, demonstrating the complementary nature of these techniques.
Asunto(s)
Aberraciones Cromosómicas , Citogenética/métodos , Interleucina-2/farmacología , Leucemia Linfocítica Crónica de Células B/genética , Oligonucleótidos/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular/efectos de los fármacos , Bandeo Cromosómico , Interpretación Estadística de Datos , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación/métodos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Translocación Genética , Células Tumorales CultivadasAsunto(s)
Leucemia Mielomonocítica Crónica/inducido químicamente , Proteína de la Leucemia Mieloide-Linfoide/genética , Osteosarcoma/terapia , Adolescente , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mielomonocítica Crónica/genética , Masculino , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/cirugíaRESUMEN
PURPOSE: The present study aimed at investigating if 2'-2' difluorodeoxycytidine (dFdC) radioenhancement was mediated by an effect on induction and/or repair of radiation-induced DNA DSBs and chromosome aberrations in cells with different intrinsic radiosensitivity. METHODS: Confluent human head and neck squamous cell carcinoma cell lines designated SCC61 and SQD9 were treated with 5 microM dFdC for 3 or 24 h prior to irradiation. DNA DSBs induction and repair were analyzed by PFGE. Radiation-induced chromosome aberrations were examined with a FISH technique. RESULTS: In both cell lines, dFdC did not modify radiation-induced DNA DSBs in a dose range between 0 and 40 Gy. After a single dose of 40 Gy, dFdC affected neither the kinetic of repair nor the residual amount of DNA DSBs up to 4 h after irradiation. Whereas dFdC did not increase the induction of chromosome aberrations, after a single dose of 5 Gy, the percentage of aberrant cells and the number of aberrations per aberrant cells were significantly higher in combination with dFdC. CONCLUSION: Our data suggest that under experimental conditions yielding substantial radioenhancement, dFdC decreases the repair of genomic lesions inducing secondary chromosome breaks but has no effect on DNA DSBs repair as measured by PFGE.