Genetic Features and TP53 Mutations in Chronic Lymphocytic Leukemia

2021 ◽  
Author(s):  
Isil Erdogan Ozunal ◽  
◽  
Tugrul Elverdi ◽  
Ayse Salihoglu ◽  
Ahmet Emre Eskazan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Tp53 Mutations ◽  
Genetic Features

Chronic lymphocytic leukemia with isochromosome 17q: An aggressive subgroup associated with TP53 mutations and complex karyotypes

2017 ◽  
Vol 409 ◽  
pp. 42-48 ◽  
Author(s):  
Rosa Collado ◽  
Anna Puiggros ◽  
José Antonio López-Guerrero ◽  
Ma José Calasanz ◽  
Ma José Larráyoz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Tp53 Mutations

scholarly journals Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3283-3283
Author(s):  
Barbara Kantorova ◽  
Jitka Malcikova ◽  
Veronika Navrkalova ◽  
Jana Smardova ◽  
Kamila Brazdilova ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
The Other ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Time To First Treatment ◽  
Hotspot Mutation

Abstract Introduction A presence of activating mutations in NOTCH1 gene has been recently associated with reduced survival and chemo-immunotherapy resistance in chronic lymphocytic leukemia (CLL). However, a prognostic significance of the NOTCH1 mutations with respect to TP53mutation status has not been fully explained yet. Methods An examined cohort included 409 patients with CLL enriched for high risk cases; in 121 patients consecutive samples were investigated. To determine the TP53 mutation status, a functional analysis of separated alleles in yeast (FASAY, exons 4-10) combined with direct sequencing was performed; the ambiguous cases were retested using an ultra-deep next generation sequencing (MiSeq platform; Illumina). The presence of NOTCH1 hotspot mutation (c.7544_7545delCT) was analyzed using direct sequencing complemented by allele-specific PCR in the selected samples. In several patients harboring concurrent NOTCH1 and TP53 mutations, single separated cancer cells were examined using multiplex PCR followed by direct sequencing. A correlation between mutation presence and patient overall survival, time to first treatment and other molecular and cytogenetic prognostic markers was assessed using Log-rank (Mantel-cox) test and Fisher's exact test, respectively. Results The NOTCH1 and TP53 mutations were detected in 16% (65/409) and 27% (110/409) of the examined patients, respectively; a coexistence of these mutations in the same blood samples was observed in 11% (19/175) of the mutated patients. The detected increased mutation frequency attributes to more unfavorable profile of the analyzed cohort; in the TP53-mutated patients missense substitutions predominated (75% of TP53 mutations). As expected, a significantly reduced overall survival in comparison to the wild-type cases (147 months) was observed in the NOTCH1-mutated (115 months; P = 0.0018), TP53-mutated (79 months; P < 0.0001) and NOTCH1-TP53-mutated patients (101 months; P = 0.0282). Since both NOTCH1 and TP53 mutations were strongly associated with an unmutated IGHV gene status (P < 0.0001 and P = 0.0007), we reanalyzed the IGHV-unmutated patients only and interestingly, the impact of simultaneous NOTCH1 and TP53 mutation presence on patient survival was missed in this case (P = 0.1478). On the other hand, in the NOTCH1 and/or TP53-mutated patients significantly reduced time to first treatment was identified as compared to the wild-type cases (41 months vs. 25 months in NOTCH1-mutated, P = 0.0075; 17 months in TP53-mutated, P < 0.0001; and 18 months in NOTCH1-TP53-mutated patients, P = 0.0003). The similar results were observed also in the subgroup of the IGHV-unmutated patients, with the exception of patients carrying sole NOTCH1 mutation (P = 0.2969). Moreover, in the NOTCH1-TP53-mutated patients an increased frequency of del(17p)(13.1) was found in comparison to the TP53-mutated patients only (72% vs. 56%); this cytogenetic defect was not detected in the patients with sole NOTCH1 mutation. Our results might indicate, that NOTCH1 mutation could preferentially co-selected with particular, less prognostic negative type of TP53 defects. Notably, in our cohort the NOTCH1 mutation predominated in the patients harboring truncating TP53 mutations localized in a C-terminal part of the TP53 gene behind the DNA-binding domain (P = 0.0128). Moreover, in one of the NOTCH1-TP53-mutated patients the analysis of separated cancer cells revealed a simultaneous presence of NOTCH1 mutation and TP53 in-frame deletion in the same CLL cell. In contrast, in the other examined NOTCH1-TP53-mutated patient the concurrent NOTCH1 mutation and TP53 missense substitution (with presumed negative impact on patient prognosis) were found in different CLL cells. Conclusions The parallel presence of NOTCH1 hotspot mutation might be detected in a significant proportion of TP53-mutated patients and it seems to be associated with less prognostic unfavorable TP53 mutations. Nevertheless, these preliminary data should be further confirmed in a large cohort of patients. This study was supported by projects VaVPI MSMT CR CZ.1.05/1.1.00/02.0068 of CEITEC, IGA MZ CR NT13493-4/2012, NT13519-4/2012 and CZ.1.07/2.3.00/30.0009. Disclosures Brychtova: Roche: Travel grants Other. Doubek:Roche: Travel grants Other.

Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial

2011 ◽  
Vol 29 (16) ◽  
pp. 2223-2229 ◽  
Author(s):  
David Gonzalez ◽  
Pilar Martinez ◽  
Rachel Wade ◽  
Sarah Hockley ◽  
David Oscier ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Data ◽  
Prognostic Value ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
Gene Tp53

Purpose TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. Patients and Methods We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. Results Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. Conclusion TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

scholarly journals THE SPECTRUM OF GENETIC DEFECTS IN CHRONIC LYMPHOCYTIC LEUKEMIA

2012 ◽  
Vol 4 (1) ◽  
pp. e2012076 ◽  
Author(s):  
Davide Rossi ◽  
Marco Fangazio ◽  
Gianluca Gaidano
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Western World ◽  
Tp53 Mutations ◽  
High Risk Disease ◽  
Risk Patients ◽  
New Biomarkers ◽  
Molecular Bases ◽  
Generation Sequencing

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and shows a remarkable heterogeneity in the clinical course. Understand the genetic basis of CLL may help in clarifying the molecular bases of this clinical heterogeneity. Recurrent chromosomal aberrations at 13q14, 12q, 11q22-q23 and 17p13, and TP53 mutations are the first genetic lesions identified as drivers of the disease. While some of these lesions are associated with poor outcome (17p13 deletion, TP53 mutations and, to a lesser extent, 11q22-q23 deletion) others are linked to a favorable course (13q14 deletion as sole aberration). Recently, next generation sequencing has revealed additional recurrent alterations in CLL targeting the NOTCH1, SF3B1, and BIRC3 genes. NOTCH1, SF3B1, and BIRC3 lesions provide: i) new insights on the mechanisms of leukemogenesis, tumor progression and chemoresistance in this leukemia; ii) new biomarkers for the identification of poor risk patients, having individually shown correlations with survival in CLL; and iii) new therapeutic targets, especially in the setting of high risk disease. This review will summarize the most important genetic aberrations in CLL and how our improved knowledge of the genome of leukemic cells may translate into improved patients' management.

A comprehensive study of TP53 mutations in chronic lymphocytic leukemia: Analysis of 1287 diagnostic and 1148 follow-up CLL samples

2011 ◽  
Vol 35 (7) ◽  
pp. 889-898 ◽  
Author(s):  
Sona Pekova ◽  
Oldrich Mazal ◽  
Radek Cmejla ◽  
David W. Hardekopf ◽  
Radek Plachy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Tp53 Mutations ◽  
Comprehensive Study

Detailed Molecular Analysis of Patients with Chronic Lymphocytic Leukemia Carrying 17p Deletions Reveals Concurrent Abnormalities with Prognostic Impact

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4577-4577
Author(s):  
Julio Delgado ◽  
Itziar Salaverría ◽  
Eriong Lee ◽  
Laura Jiménez ◽  
Alba Navarro ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
Copy Number ◽  
Prognostic Value ◽  
De Novo ◽  
Lymphocytic Leukemia ◽  
Complex Karyotype ◽  
Tp53 Mutations ◽  
Genomic Complexity ◽  
Allelic Burden

Abstract Abstract 4577 Patients with chronic lymphocytic leukemia (CLL) whose tumor cells harbor 17p deletions (17p-) by fluorescent in-situ hybridization (FISH) or chromosome banding analysis (CBA) are considered to have a poor survival. The disease is usually refractory to conventional chemotherapy and alternative therapeutic approaches are generally recommended. There is, however, a degree of clinical heterogeneity within 17p- CLL patients, as a significant proportion of them remain asymptomatic for prolonged periods of time. The aim of this study was to determine the prognostic value of concomitant molecular abnormalities in patients with 17p- CLL. Clinical and laboratory data were collected from 76 patients with 17p- CLL, detected either at diagnosis (de novo deletions, 39 patients) or over the course of the disease (acquired deletions, 37 patients). The cut-off used to define a positive FISH result was 10%, and complex karyotype was defined as the presence of 3 or more aberrations by CBA. We performed Sanger sequencing of IGHV, TP53 (exons 4–9), NOTCH1 (exon 34) and SF3B1 (exons 14–18), as well as high resolution copy number analysis using a SNP-array platform (CN-SNP). Both CBA/FISH and molecular studies were performed on samples drawn on the same date. Main biological characteristics, including CD38 and ZAP-70 expression or beta2-microglobulin (B2M), were also recorded. We evaluated the impact of these variables on time to first treatment (TTFT) and overall survival (OS) from sampling. TTFT was only evaluated in patients with de novo 17p-, and OS was evaluated in the whole cohort. Optimal cut-offs for FISH, B2M and copy number aberrations (CNAs) were calculated using maximally selected rank statistics, and were ≥25%, ≥3.5 mg/dl and ≥3, respectively (maxstat package, R, version 2.15.0). TP53 mutations were detected in 28/60 (47%) patients, and were more frequent in patients with ≥25% 17p- cells by FISH (64% vs 32%, p=0.029). CN-SNP confirmed 17p losses in only 19/68 (28%) patients and 90% of them also had concurrent TP53 mutations. 17p- by CN-SNP were mostly detected in patients with ≥25% 17p- cells by FISH [11/16 (69%)], compared to 6/49 (12%) patients with <25% cells (p<0.001). Median CNAs was 2 (range, 0–21) and was significantly higher in patients with ≥25% 17p- cells by FISH (median 3) compared to those patients with a lower allelic burden (median 1, p=0.017). Median CNAs were also higher in patients with 17p- by CN-SNP compared to those without 17p- by CN-SNP (3 vs 1, p<0.001). NOTCH1 and SF3B1 mutations were found in 8/42 (19%) and 1/20 (5%) patients, respectively. Variables predictive of a shorter TTFT in patients with de novo 17p- were unmutated IGHV genes (p=0.037), positive CD38 expression (p=0.002), positive ZAP-70 expression (p=0.010), complex karyotype by CBA (p=0.043), and ≥3 CNAs by SNP arrays (p=0.002). Multivariate analysis revealed that the presence of ≥3 CNAs was the only variable with independent prognostic value in terms of TTFT (hazard ratio [HR] 5.8, 95% confidence interval [CI] 2.0–16.7, p=0.001). Regarding OS, variables with a negative impact by univariate analysis were ≥25% 17p- cells by FISH (p=0.002), presence of TP53 mutations on the other allele (p=0.021), presence of 17p- by CN-SNP (p=0.022), unmutated IGHV genes (p=0.026), positive ZAP-70 expression (p=0.043) and elevated B2M (p=0.004). Genomic complexity was predictive of a shorter OS, but only by CBA. As such, patients with a complex karyotype had a significantly shorter OS (p=0.035), but not patients with ≥3 CNAs. Multivariate analysis revealed that ≥ 25% 17p- cells by FISH (HR 3.0, 95% CI 1.4–6.6, p=0.007) and B2M (HR 2.5, 95% CI 1.2–5.4, p=0.015) were the only variables with independent prognostic value. In conclusion, the prognosis of patients with a 17p- CLL is modulated by the allelic burden by FISH and genomic complexity. CN-SNP arrays were less sensitive than FISH in the detection of 17p losses, although the presence of ≥3 CNAs was particularly predictive of TTFT in patients with de novo 17p-. Disclosures: No relevant conflicts of interest to declare.

Clinical Impact of Clonal and Subclonal TP53, SF3B1, BIRC3, and ATM Mutations in Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4138-4138
Author(s):  
Ferran Nadeu ◽  
Julio Delgado ◽  
Cristina Royo ◽  
Tycho Bauman ◽  
Tatjana Stankovic ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Allele Frequency ◽  
Lymphocytic Leukemia ◽  
Molecular Characteristics ◽  
Prognostic Impact ◽  
Driver Genes ◽  
Germline Variants ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
The Impact

Abstract Genomic studies have provided a complete profile of somatic mutations in chronic lymphocytic leukemia (CLL). These comprehensive approaches have revealed a relatively large number of mutated genes, the adverse prognostic value of some of which has been demonstrated in a number of reports. Recent studies have shown the clinical relevance of TP53 mutations at very low allele frequency. The presence and prognostic impact of minor mutated clones of other CLL driver genes and their clonal dynamics in the evolution of the disease is not well known. The goal of this study was to explore the presence of clonal and subclonal mutations of TP53, SF3B1, BIRC3, and ATM using an ultra-deep next-generation sequencing (NGS) strategy, to define the evolution of these subclones in different time-points of the disease, and to determine their influence in the outcome of the patients. Samples from 363 untreated CLL cases were included in this study. Copy number alterations were investigated by high density SNP-arrays or by quantitative PCR in 341 and 16 cases, respectively. Targeted ultra-deep NGS of TP53 (exons 4-10), ATM (exons 2-63), BIRC3 (exons 2-9), and SF3B1 (exons 14-16 and 18), including splicing sites, was performed using the Access-Array system (Fluidigm) and sequenced in a MiSeq equipment (Illumina). This methodology combined with a robust bioinformatic analysis based on well-known available tools allowed the identification of mutations down to 0.3% of variant allele frequency (VAF). Results obtained were fully verified by orthogonal techniques. Twelve per cent of VAF was used as threshold for the classification of clonal or subclonal mutations since 12% was the cut-off for detection of mutations by Sanger sequencing. Deletions of 11q comprising ATM or BIRC3 were found in 7% of the cases and were associated with mutations of the other ATM allele in 19/26 (73%) cases and BIRC3 in 3/23 (13%). Deletions of 17p were found in 19 (5%) cases and co-existed with TP53 mutations in 15 (79%) of them. Regarding the mutational status of the studied genes, TP53 mutations were present in 11.6% of patients (7.2% clonal, 4.4% subclonal), ATM mutations in 10% (7% clonal, 1% subclonal, 2% germline mutations considered pathogenic), SF3B1 mutations in 12% (7% clonal, 5% subclonal), and BIRC3 mutations in 4% (2% clonal, 2% subclonal). These subclonal mutations had similar molecular characteristics to their respective high-allele frequency mutations supporting a comparable pathogenic effect. In this regard, clonal and subclonal SF3B1 mutations were associated with shorter time to first treatment (TTT) independently of IGHV mutations. Clonal and subclonal TP53 mutations predicted for shorter overall survival (OS) together with the IGHV mutational status, although the impact of isolated TP53 mutations (i.e. without 17p deletion) on OS was not so evident, as has been the case in other studies. In addition, the outcome of patients with clonal and subclonal BIRC3 mutations showed a similar significant shorter OS. Regarding ATM, the effect of isolated subclonal ATM mutations could not be evaluated because of their low number, but ATM mutations as a whole had a significant impact on TTT even in the absence of 11q deletions. This study also reinforces the need to study the germline of the patients to fully characterize the ATM mutations observed in the tumors. Of note, germline variants previously described as pathogenic were associated with 11q deletions, confirming the hypothesis already suggested that these germline variants may influence disease progression through loss of the otherallele. Clonal dynamics was examined in longitudinal samples of 45 CLL patients. We confirmed the expansion of most TP53 mutated clones after therapy. However, both TP53 and SF3B1 mutations expanded also before any therapy in some patients, indicating that progressive dynamics of these clones is not only dependent on therapy selection. On the contrary, small ATM mutated clones seemed to be more stable. Although the number of cases is limited, we observed that clonal evolution in longitudinal samples had an unfavorable impact on OS. In conclusion, this study shows the presence of a high number of subclonal mutations of different driver genes in CLL and provides insights on the impact of these mutations on the outcome of the patients. These findings suggest that the characterization of the subclonal architecture may be relevant for a better management of CLL patients. Disclosures No relevant conflicts of interest to declare.

TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes

2016 ◽  
Vol 139 (8) ◽  
pp. 1759-1763 ◽  
Author(s):  
Gregory Lazarian ◽  
Eugen Tausch ◽  
Virginie Eclache ◽  
Amel Sebaa ◽  
Vincent Bianchi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Lymphocytic Leukemia ◽  
Tp53 Mutations

Chronic Lymphocytic Leukemia: State of the Art and Beyond

2014 ◽  
Vol 12 (5S) ◽  
pp. 801-803
Author(s):  
John C. Byrd
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
State Of The Art ◽  
Lymphocytic Leukemia ◽  
Newly Diagnosed ◽  
Treatment Standard ◽  
Genetic Features ◽  
Treatment Paradigm ◽  
Genomic Studies ◽  
Poor Outcomes

In the treatment of chronic lymphocytic leukemia (CLL), select genomic studies can assist in risk stratification of newly diagnosed patients. Chemoimmunotherapy targeting CD20 offers a survival advantage in symptomatic patients both with and without these high-risk genetic features, though patients with del(17p13.1) have poor outcomes and require specific intervention. Obinutuzumab plus chlorambucil is a treatment standard for untreated elderly patients and is superior to rituximab plus chlorambucil. In the setting of relapsed CLL, the new kinase inhibitors have the potential to completely change the treatment paradigm of CLL.

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