RESUMO
The significance of chromosomal translocations (CTRAs) and karyotype complexity (KC) in chronic lymphocytic leukemia (CLL) remains uncertain. To gain insight into these issues, we evaluated a series of 1001 CLL cases with reliable classic cytogenetic data obtained within 6 months from diagnosis before any treatment. Overall, 320 cases were found to carry ≥ 1 CTRAs. The most frequent chromosome breakpoints were 13q, followed by 14q, 18q, 17q, and 17p; notably, CTRAs involving chromosome 13q showed a wide spectrum of translocation partners. KC (≥ 3 aberrations) was detected in 157 cases and significantly (P < 0.005) associated with unmutated IGHV genes and aberrations of chromosome 17p. Furthermore, it was identified as an independent prognostic factor for shorter time-to-first-treatment. CTRAs were assigned to two categories (i) CTRAs present in the context of KC, often with involvement of chromosome 17p aberrations, occurring mostly in CLL with unmutated IGHV genes; in such cases, we found that KC rather than the presence of CTRAs per se negatively impacts on survival; (ii) CTRAs in cases without KC, having limited if any impact on survival. On this evidence, we propose that all CTRAs in CLL are not equivalent but rather develop by different processes and are associated with distinct clonal behavior.
Assuntos
Cariótipo , Leucemia Linfocítica Crônica de Células B/genética , Translocação Genética , Técnicas de Cultura de Células/métodos , Aberrações Cromossômicas , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Cromossomos Humanos/genética , Cromossomos Humanos/ultraestrutura , Feminino , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Humanos , Hibridização in Situ Fluorescente , Interfase , Estimativa de Kaplan-Meier , Cariotipagem/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Modelos de Riscos Proporcionais , Células Tumorais CultivadasRESUMO
Deletion of ATM detected by fluorescent in situ hybridization (FISH) in chronic lymphocytic leukemia predicts short treatment free survival and poor outcome following alkylator/purine analogue therapy. We describe five cases, with a diminished ATM FISH signal, investigated by TP53 mutation/dysfunction studies and single nucleotide polymorphism (SNP) array. The diminished signal represented loss of the ATM gene, which could have been missed were the cases not further investigated. These rare cases highlight the need for careful consideration of the choice of probe and interpretation of unusual signal patterns in FISH screening. We define a new minimal region of deletion at 11q22.3.
Assuntos
Proteínas de Ciclo Celular/genética , Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Sondas de DNA , Proteínas de Ligação a DNA/genética , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genéticaRESUMO
This study evaluates the prognostic significance of genetic abnormalities (detected at or shortly after presentation), clinical stage, lymphocyte morphology, CD38 expression, and IGVH gene status in 205 patients with chronic lymphocytic leukemia (B-CLL). Deletion of chromosome 11q23, absence of a deletion of chromosome 13q14, atypical lymphocyte morphology, and more than 30% CD38 expression are significantly associated with the presence of unmutated IGVH genes. Advanced stage, male sex, atypical morphology, more than 30% CD38 expression, trisomy 12, deletion of chromosome 11q23, loss or mutation of the p53 gene, and unmutated IGVH genes are all poor prognostic factors in a univariate analysis. However, only 98% or more homology of IGVH genes to the germline sequence, loss or mutation of the p53 gene, and clinical stage retain prognostic significance in a multivariate analysis. The median survival of patients with mutated IGVH genes, unmutated IGVH genes, and loss or mutation of the p53 gene regardless of IGVH gene status is 310, 119, and 47 months, respectively. These data should facilitate the design of new trials for the management of patients presenting with advanced disease or poor prognosis early stage disease.