ABSTRACT
Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.
Subject(s)
Cyclophosphamide/administration & dosage , Gene Expression Regulation, Leukemic , Immunotherapy/methods , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Mutation , Rituximab/administration & dosage , Vidarabine/analogs & derivatives , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , DNA Mutational Analysis , Female , Genomics , Humans , Male , Middle Aged , RNA Splicing , Vidarabine/administration & dosageABSTRACT
Chronic lymphocytic leukaemia is the most prevalent leukaemia in Western countries. It is an incurable disease characterized by a highly variable clinical course. Chronic lymphocytic leukaemia is an ideal model for studying clonal heterogeneity and dynamics during cancer progression, response to therapy and/or relapse because the disease usually develops over several years. Here we report an analysis by deep sequencing of sequential samples taken at different times from the affected organs of two patients with 12- and 7-year disease courses, respectively. One of the patients followed a linear pattern of clonal evolution, acquiring and selecting new mutations in response to salvage therapy and/or allogeneic transplantation, while the other suffered loss of cellular tumoral clones during progression and histological transformation.
Subject(s)
Clonal Evolution , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Clone Cells , Fatal Outcome , Gene Frequency/genetics , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Male , Middle Aged , Mutagenesis/genetics , Mutation/genetics , Exome SequencingABSTRACT
The prognostic impact of biallelic ATM abnormalities (ATM mutation and concurrent 11q deletion) remains unknown. We studied ATM, BIRC3, SF3B1, and NOTCH1 genes in 118 treatment-naïve CLL patients at diagnosis. Patients with biallelic ATM alteration had a similar time to first treatment (TTFT) and shorter overall survival (OS) compared with patients with isolated 11q deletion and shorter TTFT and OS when compared to patients with wild-type ATM. Furthermore, biallelic ATM alteration (HR: 6.4; p ≤ 0.007) was significantly associated with an increased risk of death similar to p53 deletion (HR: 6.1; p ≤ 0.004), superior to 11q deletion alone (HR: 2.8; p ≤ 0.022) and independent of other significant parameters such as age, advanced clinical stage, and complex karyotype. Our results suggest the identification of ATM mutations in CLL patients with 11q deletion at diagnosis is clinically relevant and predicts disease progression, poor response to the treatment, and reduced OS independent of other molecular prognostic factors.
Subject(s)
Alleles , Ataxia Telangiectasia Mutated Proteins/genetics , Gene Deletion , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Mutation , Tumor Suppressor Protein p53 , Aged , Aged, 80 and over , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 17 , DNA Mutational Analysis , Female , Gene Frequency , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Prognosis , Proportional Hazards ModelsABSTRACT
Vascular endothelial growth factor (VEGF)-mediated angiogenesis contributes to the pathogenesis of B-cell chronic lymphocytic leukaemia (CLL). We investigated the impact of VEGFA gene diversity on the clinical outcome of patients with this disease. A VEGFA haplotype conformed by positions rs699947 (-1540C>A), rs833061 (-460T>C) and rs2010963 (405C>G) and two additional single-nucleotide polymorphisms (SNPs), rs3025039 (936C>T) and rs25648 (1032C>T), were analysed in 239 patients at the time of their CLL diagnosis. Here, we showed that homozygosity for rs699947/rs833061/rs2010963 ACG haplotype (ACG+/+ genotype) correlated with a reduced survival in CLL patients (ACG+/+ vs other genotypes: HRâ=â2.3, pâ=â0.002; recessive model). In multivariate analysis, the ACG+/+ genotype was identified as a novel independent prognostic factor (HRâ=â2.1, pâ=â0.005). Moreover, ACG homozygosity subdivided patients with CLL with otherwise indolent parameters into prognostic subgroups with different outcomes. Specifically, patients carrying the ACG+/+ genotype with mutated IgVH, very low and low-risk cytogenetics, initial clinical stage, CD38 negative status or early age at diagnosis showed a shorter survival (ACG+/+ vs other genotypes: HRâ=â3.5, pâ=â0.035; HRâ=â3.4, pâ=â0.001; HRâ=â2.2, pâ=â0.035; HRâ=â3.4, pâ=â0.0001 and HRâ=â3.1, pâ=â0.009, respectively). In conclusion, VEGFA ACG+/+ genotype confers an adverse effect in overall survival in CLL patients with an indolent course of the disease. These observations support the biological and prognostic implications of VEGFA genetics in CLL.
