RESUMO
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.
Assuntos
Linfoma de Burkitt/genética , Aberrações Cromossômicas , Cromossomos Humanos , Rearranjo Gênico , Genes myc , Linfoma de Células B/genética , Cariótipo Anormal , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , MasculinoAssuntos
Proteínas de Ciclo Celular/genética , Fusão Gênica , Janus Quinase 2/genética , Proteína de Leucina Linfoide-Mieloide/genética , Inversão de Sequência , Trombocitemia Essencial/genética , Idoso de 80 Anos ou mais , Substituição de Aminoácidos/fisiologia , Sequência de Bases , Crise Blástica/patologia , Fusão Gênica/fisiologia , Histona-Lisina N-Metiltransferase , Humanos , Masculino , Proteínas Nucleares , Fenilalanina/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Proteínas de Ligação a RNA , Inversão de Sequência/fisiologia , Trombocitemia Essencial/patologia , Valina/genéticaRESUMO
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.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Proteínas de Ligação a DNA/genética , Neoplasias Hematológicas/genética , Fatores de Transcrição/genética , Linhagem Celular , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único , TelômeroAssuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 19 , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Miosina Tipo I/genética , Translocação Genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 19/genética , Frequência do Gene , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Proteínas de Fusão Oncogênica/genética , Recidiva , Translocação Genética/fisiologiaAssuntos
Cromossomos Humanos Par 1/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-abl/genética , Precursores de RNA/genética , Proteínas de Ligação a RNA/genética , Adulto , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Fator de Processamento Associado a PTB , RNA Mensageiro/genética , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemAssuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Variação Genética/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/etiologia , Proteínas de Fusão Oncogênica/genética , Translocação Genética/genética , Idoso , Proteína p300 Associada a E1A/genética , Histona-Lisina N-Metiltransferase , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Proteína de Leucina Linfoide-Mieloide/genéticaRESUMO
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.
Assuntos
Aberrações Cromossômicas , Citogenética/métodos , Interleucina-2/farmacologia , Leucemia Linfocítica Crônica de Células B/genética , Oligonucleotídeos/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/efeitos dos fármacos , Bandeamento Cromossômico , Interpretação Estatística de Dados , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Translocação Genética , Células Tumorais CultivadasAssuntos
Leucemia Mielomonocítica Crônica/induzido quimicamente , Proteína de Leucina Linfoide-Mieloide/genética , Osteossarcoma/terapia , Adolescente , Histona-Lisina N-Metiltransferase , Humanos , Leucemia Mielomonocítica Crônica/genética , Masculino , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/cirurgiaRESUMO
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.
