59 results on '"Pavlova, Sarka"'
Search Results
52. Low-Burden TP53Mutations Occur in Chronic Phase of Myeloproliferative Neoplasms Regardless of Hydroxyurea Administration, Disease Type, and JAK2Status
- Author
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Kubesova, Blanka, Pavlova, Sarka, Malcikova, Jitka, Kabathova, Jitka, Radova, Lenka, Tom, Nikola, Tichy, Boris, Plevova, Karla, Kantorova, Barbara, Fiedorova, Kristyna, Kissova, Jarmila, Gisslinger, Bettina, Gisslinger, Heinz, Mayer, Jiri, Kralovics, Robert, Pospisilova, Sarka, and Doubek, Michael
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- 2016
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53. Prognostic Impact of NOTCH1Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia
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Kantorova, Barbara, Malcikova, Jitka, Navrkalova, Veronika, Smardova, Jana, Brazdilova, Kamila, Plevova, Karla, Diviskova, Eva, Borsky, Marek, Pavlova, Sarka, Tom, Nikola, Pal, Karol, Trbusek, Martin, Oltova, Alexandra, Brychtova, Yvona, Doubek, Michael, Mayer, Jiri, and Pospisilova, Sarka
- Abstract
Introduction
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- 2014
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54. Clonal Evolution and Therapy Related Selection Of TP53Mutations In Chronic Lymphocytic Leukemia Patients
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Plevova, Karla, Malcikova, Jitka, Trbusek, Martin, Pavlova, Sarka, Sebejova, Ludmila, Tichy, Boris, Doubek, Michael, Brychtova, Yvona, Mayer, Jiri, and Pospisilova, Sarka
- Abstract
Recent studies of clonal evolution in chronic lymphocytic leukemia (CLL) show that new copy number alterations (CNAs) emerge in disease relapse in about 30% of cases. Furthermore, selection of TP53mutations (mut-TP53) was recognized as a therapy related event in approximately one fifth of treated CLL patients and was associated with higher disease aggressiveness and inferior clinical outcome. However genomic abnormalities accompanying mut-TP53selection have not been described so far. Therefore, we analyzed clonal evolution of leukemic cells derived from patients who acquired a new TP53mutation after therapy. TP53analysis was performed in consecutive samples by FASAY and direct sequencing. Genomic DNA was isolated from separated CD19+ or mononuclear cells and analyzed using Affymetrix arrays (Cytogenetics 2.7M, or CytoScan High Density). Array results were compared with I-FISH and metaphase cytogenetics based on CpG/IL-2 stimulation. We identified 38 CLL patients with intact TP53gene before therapy but with newly acquired mut-TP53during disease relapse. Out of this specific cohort, 18 cases (47%; Cohort I) with available pre-treatment and relapse material were selected for the microarray analysis of clonal and subclonal CNAs and copy number neutral loss of heterozygosity (cnLOH). Median interval between collection of the pre-treatment and relapsed samples was 39 months (range 14-81 months), patients received 1-4 lines of therapy in the meantime (median 2 lines). In addition, a control group of 13 chemorefractory patients was analyzed in the same manner: 8 harbored mut-TP53from diagnosis (Cohort II) and 5 manifested wild-type TP53(wt-TP53) during the whole follow-up (Cohort III) (median interval 19 vs. 60 months; median number of therapies 2 vs. 3 in the meantime). Following recurrent aberrations were detected in initial samples from Cohort I: gains in 2p (2 pts), deletions in 11q22 (5 pts), 13q14 (9 pts), 14q24 (2 pts), and 17p13 (2 pts), and trisomy 12 (2 pts). Interestingly, no difference in initial genomic complexity (defined by ≥3 CNAs in the first sample) was observed between Cohorts I and III, i.e., the patients with selection of mut-TP53and control wt-TP53cases (12/18; 67% vs. 4/5; 80%). This observation may suggest that factors other than genomic complexity predispose to selection of new TP53mutations. Concerning the relapsed samples, patients with mut-TP53selection acquired on average the highest number of additional chromosomal defects per case [5.5 changes per patient vs. 3 changes in Cohort III (always wt-TP53) vs. 2.5 changes in Cohort II (always mut-TP53)]. In 10/18 (56%) patients from Cohort I, mut-TP53selection was accompanied by inactivation of the other allele through either deletion (9 pts) or cnLOH (1 pt). Further, the heterozygous mutation accompanied by intact second allele was selected in 6/18 patients (33%), and in the remaining 2 patients (11%), deletion of the second allele was already present in initial sample. Regarding the other aberrations accompanying mut-TP53appearance, we observed co-selection of monoallelic del(13q) in 4/9 initially 13q-intact cases and evolution from mono- to biallelic del(13q) in 1/9 initially 13q-monoallelic cases. This observation seems to be in contrast with the published data showing a relative stability of del13q14, or even displacement of the corresponding clones with this deletion in samples having high genomic complexity. In our cohort, we observed del(13q) elimination in disease relapse in one case only. In both control cohorts, no evolution of 13q14 locus was detected. Furthermore, complex deletions evolved on chromosome 6 in 3/18 (17%) patients in Cohort I. The region was also affected in Cohort II (always mut-TP53) but not in Cohort III (always wt-TP53), which suggests that emergence of CNAs on chromosome 6 might be associated with TP53inactivation in general. Other recurrent CNAs emerging in patients with mut-TP53selection were amp(2p), del(4p), del(9q21) and del(18p); each detected in 3/18 cases. To summarize, selection of TP53defects during CLL relapse seems to be accompanied by accumulation of specific CNAs, mainly deletions. We assume that these CNAs may be a consequence of genomic instability generally associated with TP53defects, but these CNAs may potentially also drive disease aggressiveness. Supported by CZ.1.05/1.1.00/02.0068, MSM0021622430, MUNI/A/0723/2012, NT13493-4/2012, NT13519-4/2012.
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- 2013
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55. LYmphoid NeXt-Generation Sequencing (LYNX) Panel: A Comprehensive Capture-Based Sequencing Tool for the Analysis of Prognostic and Predictive Markers in Lymphoid Malignancies.
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Navrkalova V, Plevova K, Hynst J, Pal K, Mareckova A, Reigl T, Jelinkova H, Vrzalova Z, Stranska K, Pavlova S, Panovska A, Janikova A, Doubek M, Kotaskova J, and Pospisilova S
- Subjects
- Chromosome Aberrations, Computational Biology methods, DNA Copy Number Variations, Genetic Variation, Genomics methods, Humans, INDEL Mutation, Molecular Diagnostic Techniques, Prognosis, Translocation, Genetic, Biomarkers, Tumor, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing methods, Leukemia, Lymphoid diagnosis, Leukemia, Lymphoid genetics, Lymphoma diagnosis, Lymphoma genetics
- Abstract
B-cell neoplasms represent a clinically heterogeneous group of hematologic malignancies with considerably diverse genomic architecture recently endorsed by next-generation sequencing (NGS) studies. Because multiple genetic defects have a potential or confirmed clinical impact, a tendency toward more comprehensive testing of diagnostic, prognostic, and predictive markers is desired. This study introduces the design, validation, and implementation of an integrative, custom-designed, capture-based NGS panel titled LYmphoid NeXt-generation sequencing (LYNX) for the analysis of standard and novel molecular markers in the most common lymphoid neoplasms (chronic lymphocytic leukemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma). A single LYNX test provides the following: i) accurate detection of mutations in all coding exons and splice sites of 70 lymphoma-related genes with a sensitivity of 5% variant allele frequency, ii) reliable identification of large genome-wide (≥6 Mb) and recurrent chromosomal aberrations (≥300 kb) in at least 20% of the clonal cell fraction, iii) the assessment of immunoglobulin and T-cell receptor gene rearrangements, and iv) lymphoma-specific translocation detection. Dedicated bioinformatic pipelines were designed to detect all markers mentioned above. The LYNX panel represents a comprehensive, up-to-date tool suitable for routine testing of lymphoid neoplasms with research and clinical applicability. It allows a wide adoption of capture-based targeted NGS in clinical practice and personalized management of patients with lymphoproliferative diseases., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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56. Detection and Functional Analysis of TP53 Mutations in CLL.
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Pavlova S, Smardova J, Tom N, and Trbusek M
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- Alleles, DNA Mutational Analysis instrumentation, DNA Mutational Analysis methods, Genes, Reporter genetics, High-Throughput Nucleotide Sequencing instrumentation, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation, Neoplastic Cells, Circulating pathology, Saccharomyces cerevisiae genetics, Transfection instrumentation, Transfection methods, High-Throughput Nucleotide Sequencing methods, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Chronic lymphocytic leukemia (CLL) represents a prototype disease in which TP53 gene defects lead to inferior prognosis. Here, we present two distinct methodologies which can be used to identify TP53 mutations in CLL patients; both protocols are primarily intended for research purposes. The functional analysis of separated alleles in yeast (FASAY) can be flexibly adapted to a variable number of samples and provides an immediate functional readout of identified mutations. Amplicon-based next-generation sequencing then allows for a high throughput and accurately detects subclonal TP53 variants (sensitivity <1% of mutated cells).
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- 2019
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57. MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis.
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Benner A, Mansouri L, Rossi D, Majid A, Willander K, Parker A, Bond G, Pavlova S, Nückel H, Merkel O, Ghia P, Montserrat E, Kaderi MA, Rosenquist R, Gaidano G, Dyer MJ, Söderkvist P, Linderholm M, Oscier D, Tvaruzkova Z, Pospisilova S, Dührsen U, Greil R, Döhner H, Stilgenbauer S, and Zenz T
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- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Young Adult, Databases, Factual trends, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins c-mdm2 genetics
- Abstract
A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies., (Copyright© Ferrata Storti Foundation.)
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- 2014
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58. Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones.
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Plevova K, Francova HS, Burckova K, Brychtova Y, Doubek M, Pavlova S, Malcikova J, Mayer J, Tichy B, and Pospisilova S
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- Disease-Free Survival, Female, Humans, Male, Survival Rate, B-Lymphocytes, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Mutation, Somatic Hypermutation, Immunoglobulin, Tumor Suppressor Protein p53 genetics
- Abstract
In chronic lymphocytic leukemia, usually a monoclonal disease, multiple productive immunoglobulin heavy chain gene rearrangements are identified sporadically. Prognostication of such cases based on immunoglobulin heavy variable gene mutational status can be problematic, especially if the different rearrangements have discordant mutational status. To gain insight into the possible biological mechanisms underlying the origin of the multiple rearrangements, we performed a comprehensive immunogenetic and immunophenotypic characterization of 31 cases with the multiple rearrangements identified in a cohort of 1147 patients with chronic lymphocytic leukemia. For the majority of cases (25/31), we provide evidence of the co-existence of at least two B lymphocyte clones with a chronic lymphocytic leukemia phenotype. We also identified clonal drifts in serial samples, likely driven by selection forces. More specifically, higher immunoglobulin variable gene identity to germline and longer complementarity determining region 3 were preferred in persistent or newly appearing clones, a phenomenon more pronounced in patients with stereotyped B-cell receptors. Finally, we report that other factors, such as TP53 gene defects and therapy administration, influence clonal selection. Our findings are relevant to clonal evolution in the context of antigen stimulation and transition of monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia.
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- 2014
- Full Text
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59. ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin.
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Navrkalova V, Sebejova L, Zemanova J, Kminkova J, Kubesova B, Malcikova J, Mraz M, Smardova J, Pavlova S, Doubek M, Brychtova Y, Potesil D, Nemethova V, Mayer J, Pospisilova S, and Trbusek M
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- Adult, Aged, Aged, 80 and over, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins physiology, Cell Survival physiology, Chromosome Deletion, Chromosomes, Human, Pair 11 genetics, Cohort Studies, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear pathology, Male, Middle Aged, Retrospective Studies, Ataxia Telangiectasia Mutated Proteins genetics, Cell Survival drug effects, Doxorubicin pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mutation genetics
- Abstract
ATM abnormalities are frequent in chronic lymphocytic leukemia and represent an important prognostic factor. Sole 11q deletion does not result in ATM inactivation by contrast to biallelic defects involving mutations. Therefore, the analysis of ATM mutations and their functional impact is crucial. In this study, we analyzed ATM mutations in predominantly high-risk patients using: i) resequencing microarray and direct sequencing; ii) Western blot for total ATM level; iii) functional test based on p21 gene induction after parallel treatment of leukemic cells with fludarabine and doxorubicin. ATM dysfunction leads to impaired p21 induction after doxorubicin exposure. We detected ATM mutation in 16% (22 of 140) of patients, and all mutated samples manifested demonstrable ATM defect (impaired p21 upregulation after doxorubicin and/or null protein level). Loss of ATM function in mutated samples was also evidenced through defective p53 pathway activation after ionizing radiation exposure. ATM mutation frequency was 34% in patients with 11q deletion, 4% in the TP53-defected group, and 8% in wild-type patients. Our functional test, convenient for routine use, showed high sensitivity (80%) and specificity (97%) for ATM mutations prediction. Only cells with ATM mutation, but not those with sole 11q deletion, were resistant to doxorubicin. As far as fludarabine is concerned, this difference was not observed. Interestingly, patients from both these groups experienced nearly identical time to first treatment. In conclusion, ATM mutations either alone or in combination with 11q deletion uniformly led to demonstrable ATM dysfunction in patients with chronic lymphocytic leukemia and mutation presence can be predicted by the functional test using doxorubicin.
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- 2013
- Full Text
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