Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

[Cytogenetic and molecular monitoring of chronic myeloid leukemia]. / A krónikus myeloid leukaemia citogenetikai es molekuláris monitorozása.

The t(9;22) translocation, which results in a fusion protein with abnormal tyrosine-kinase activity, plays a central role in the pathogenesis of chronic myeloid leukemia. The selective inhibition of this chimeric protein with imatinib-mesylate is an efficient therapeutic option, haematologic and cytogenetic responses can be achieved in most of the patients. The primary goal of monitoring the disease is to assess the efficiency of the therapy, to highlight those patients, whose survival may be improved by modifying treatment. Three methods are widely used for the genetic monitoring of chronic myeloid leukemia. With karyotyping, the proliferating bone marrow cells can be evaluated. The use of fluorescent in situ hybridization makes the cytogenetic analysis of each cell within the sample possible. Real-time quantitative polymerase chain reaction is capable of quantifying residual leukemia far below the sensitivity of cytogenetics. The results of these three methods have different biological meanings, thus, for the interpretation of the results, the knowledge of the characteristics, the benefits and the draw-backs of the methods is required. The present study shows the most important characteristics of these methods based on the literature and data acquired from 1165 samples of 197 patients detected by the authors.