RESUMEN
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.
Asunto(s)
Cariotipo , Leucemia Linfocítica Crónica de Células B/genética , Translocación Genética , Técnicas de Cultivo de Célula/métodos , Aberraciones Cromosómicas , Puntos de Rotura del Cromosoma , Deleción Cromosómica , Cromosomas Humanos/genética , Cromosomas Humanos/ultraestructura , Femenino , Reordenamiento Génico de Cadena Pesada de Linfocito B , Humanos , Hibridación Fluorescente in Situ , Interfase , Estimación de Kaplan-Meier , Cariotipificación/métodos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Modelos de Riesgos Proporcionales , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Proteínas de Ciclo Celular/genética , Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Sondas de ADN , Proteínas de Unión al ADN/genética , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano de 80 o más Años , Proteínas de la Ataxia Telangiectasia Mutada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
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.