Clinical impact of the subclonal architecture and mutational complexity in chronic lymphocytic leukemia

Abstract

Genome studies of chronic lymphocytic leukemia (CLL) have revealed the remarkable subclonal heterogeneity of the tumors, but the clinical implications of this phenomenon are not well known. We assessed the mutational status of 28 CLL driver genes by deep-targeted next-generation sequencing and copy number alterations (CNA) in 406 previously untreated patients and 48 sequential samples. We detected small subclonal mutations (0.6–25% of cells) in nearly all genes (26/28), and they were the sole alteration in 22% of the mutated cases. CNA tended to be acquired early in the evolution of the disease and remained stable, whereas the mutational heterogeneity increased in a subset of tumors. The prognostic impact of different genes was related to the size of the mutated clone. Combining mutations and CNA, we observed that the accumulation of driver alterations (mutational complexity) gradually shortened the time to first treatment independently of the clonal architecture, IGHV status and Binet stage. Conversely, the overall survival was associated with the increasing subclonal diversity of the tumors but it was related to the age of patients, IGHV and TP53 status of the tumors. In conclusion, our study reveals that both the mutational complexity and subclonal diversity influence the evolution of CLL.

Dissection of subclonal evolution by temporal mutation profiling in chronic lymphocytic leukemia patients treated with ibrutinib

“…reporting for the first time that mutations emerging subclonally are more common in CLL as compared to clonal mutations, and the extent of subclonal heterogeneity has an influence on the survival of CLL patients. 28 This was confirmed and extended by Leeksma et al documenting increased subclonal heterogeneity and significant enrichment of recurrent gene mutations in chemotherapy refractory patients as compared to treatment naïve cases, in a cohort of 643 patients. 29 Although in clinical terms, response to ibrutinib appears to be independent of TP53 aberrations, patients with TP53 defects relapse more frequently, suggesting a complex biology behind TP53 deregulation.…”

“…The common presence of subclonal mutations detected in virtually all genes analyzed in our study is in line with a recent observation by Nadeu et al . reporting for the first time that mutations emerging subclonally are more common in CLL as compared to clonal mutations, and the extent of subclonal heterogeneity has an influence on the survival of CLL patients . This was confirmed and extended by Leeksma et al .…”

“…S6). While in Patient #10, the disease progression was associated with the known BTK Cys481Ser and PLCG2 Asp993His mutations, in Patient #9 and Patient #17, the previously unreported BTK Gln516Lys and Arg490His mutations appeared to be linked with disease progression (Fig. a , Supporting Information Fig.…”

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

“…Nfkbie loss cooperates with MYD88 signaling MYD88 codes for an proximal signaling adaptor downstream of IL-1R and mammalian TLRs. Mutations in MYD88, essentially the missense p.L265P mutation, are observed in a wide range of B-cell malignancies 8,10,13,[35][36][37][38][39] . They have been shown to activate the JAK and NF-κB pathways 36 .…”

Identification of prognostic parameters in CLL with no abnormalities detected by chromosome banding and FISH analyses

“…Patients with higher tumour load, i.e. higher percentage of CLL cells, are likely to have more advanced disease and a more aggressive behaviour showing more aberrations and subclones at genomic levels (Nadeu et al , ). Supporting this hypothesis, the multivariate analysis regarding TTT showed that the number of genomic array aberrations was related to a worse outcome independently from the percentage of CLL cells.…”