scholarly journals A TP53-mutáció-analízis jelentősége krónikus lymphocytás leukaemiában

2017 ◽  
Vol 158 (6) ◽  
pp. 220-228
Author(s):  
Viktória Fésüs ◽  
Dóra Marosvári ◽  
Béla Kajtár ◽  
Péter Attila Király ◽  
Judit Demeter ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukaemia ◽  
Mutation Analysis ◽  
Sanger Sequencing ◽  
Tp53 Mutation ◽  
Lymphocytic Leukaemia ◽  
Tp53 Mutations ◽  
Risk Patients ◽  
Innovative Medicine ◽  
Made In

Abstract: Introduction: In recent years much progress has been made in the therapy of chronic lymphocytic leukaemia, as the new innovative medicine proved to be effective in managing patients carrying TP53 abnormalities. To identify all these patients, it is essential to screen for both forms of TP53 defects, including both 17p deletions and TP53 mutations. Aim: The aim of this study was to determine the frequency of TP53 mutations and their association with 17p deletions in a large Hungarian cohort of 196 patients suffering from chronic lymphocytic leukaemia. Method: We performed mutation analysis of TP53 (exons 3–10) using Sanger sequencing. Results: TP53 mutations were present in 15.8% of patients, half of which were associated with 17p deletion. By analysing both forms, TP53 defect was identified in 25.4% of the patients. Conclusions: Our study demonstrates that by performing a TP53 mutation analysis, an additional 10% of high-risk patients can be detected. Orv. Hetil., 2017, 158(6), 220–228.

scholarly journals Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study

2014 ◽  
Vol 15 (10) ◽  
pp. 1090-1099 ◽  
Author(s):  
Jan A Burger ◽  
Michael J Keating ◽  
William G Wierda ◽  
Elena Hartmann ◽  
Julia Hoellenriegel ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Phase 2 ◽  
Phase 2 Study

scholarly journals Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Treatment in Dual Expressor Diffuse Large B-Cell and Double/Triple Hit Lymphomas: TP53 Mutations Influence on Clinical Outcome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4116-4116
Author(s):  
Anna Dodero ◽  
Anna Guidetti ◽  
Fabrizio Marino ◽  
Cristiana Carniti ◽  
Stefania Banfi ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Poor Prognosis ◽  
Tp53 Mutation ◽  
Advisory Committees ◽  
Tp53 Mutations ◽  
Travel Costs ◽  
Large B Cell

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

TP53 Abnormalities in Chronic Lymphocytic Leukemia Exhibit a Disease Specific Profile: Meta-Analysis of 270 Mutations.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2077-2077
Author(s):  
Thorsten Zenz ◽  
Jana Smadova ◽  
Dominik Vollmer ◽  
Martin Trbusek ◽  
Axel Benner ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Tp53 Mutation ◽  
Hot Spot ◽  
Statistical Significance ◽  
Residual Activity ◽  
Missense Mutations ◽  
Tp53 Mutations ◽  
Cpg Sites ◽  
Frame Shift ◽  
Mutation Pattern

Abstract TP53 mutations have been shown to occur in 5–40% of CLL patients depending on the clinical background (early stage/refractory disease). They are associated with a poor response to standard chemotherapy with alkylators and purine analogues and dismal clinical course. Because previous studies have examined small cohorts without detailed molecular characterization, the exact TP53 mutation profile and a correlation of TP53 mutation pattern, allele status and associated molecular genetics has not been possible. We performed a large scale mutation analysis of TP53 at four centres and pooled the data to characterize the pattern of TP53 mutations in CLL. The methods of mutational analysis included DHPLC (n=149 mutations), FASAY assay (n=63), direct sequencing (n=28) and a TP53 custom re-sequencing chip (n=30). We performed a comparison to a group of 463 patients without TP53 mutation. We found 270 mutations in 256 patients with CLL (14 with 2 mutations) out of over 1000 screened cases. Transversions, small deletions and insertions were observed less commonly (86/270; 44/270; 9/270 resp.). Missense mutations appeared in 74% of cases, compared to frameshift (20%), nonsense (4%) and splice site (2%) mutations. As expected, the majority (246/270) of mutations were located in the DNA binding domain of p53, predominantly represented by missense mutations (80%). Outside this central core domain, frame-shift (52%) and nonsense mutations (26%) were more frequent. Transitions were found in 131 of 270 mutations, with only 41 occurring at methylated CpG sites (15%). Interestingly, the number of G-A mutations was markedly higher in comparison with C-T mutations at the CpGs (27 vs. 14). Since the former alteration may reflect a C-T transition on non-coding, transcribed DNA strand, we hypothesize that these mutations might be selected for during a prolonged G1-phase, which is characteristic for CLL cells. Genomic aberrations detected by FISH were available for 261/270 cases. Most mutations (201/270) were accompanied by deletion of the other allele (17p-). Nonetheless, TP53 mutations were also found in cases with no aberrations (n=18) and 13q- as the sole abnormality (n=24). There appeared to be a higher frequency of frameshift mutations in the 17p- subgroup (22% vs. 13%) although the comparison did not reach statistical significance. Interestingly, trisomy 12 (without 17p- or 11q-) was only found in a single case with TP53 mutation compared to 54/463 in the cohort without mutation (P<0.0001). We quite frequently observed a deletion 11q- (36/270) accompanying the abnormalities of one (14/60) as well as of both (22/201) TP53 alleles (mutation/deletion). 11q deletion may not be a simple alternative to p53 inactivation, as it has been proposed previously. Chemotherapy before mutation analysis was noted in 106 cases. The mutational profile was not different in the cohorts with and without prior therapy suggesting that the mechanism underlying the development of mutations may be similar independent of treatment. When comparing the predicted functional activity of the mutated TP53 in different cytogenetic subgroups (http://p53.free.fr/Database/p53_recomendations.html) we observed a significantly lower residual activity (WAF1 promotor) of the missense mutations in the 17p- subgroup compared to the patients with 13q- (single) and a TP53 mutation (median 6,815 vs. 10,31 p<0,0001). Seventy percent of missense mutations (140/201) were located in 30 different codons. The amino acids most frequently mutated were at positions 179, 209, 248 and 273. This indicates that the classical hot spots are also commonly mutated in CLL. Codons 175, 248, and 273 made up for 11% of the mutations, but we identified three other commonly mutated codons (179, 209, 220) that also made up for 10% of the mutations in CLL. The mutation pattern of TP53 shows a comparatively small amount of transitions at CpG sites indicating a relatively negligible contribution of endogenous mutability at methylated cytosine. In addition, CLL is characterized by a high incidence of deleterious frame-shift mutations compared to other cancers. The high frequency of mutations at codon 209 in our cohort suggests this as a new hot spot of TP53 abnormalities associated with CLL.

TP53 Mutations Are Restricted Predominantly to 5q- Syndrome and Myelodysplastic Syndrome Patients with Complex Cytogenetics, and Correlate with Adverse Prognosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 792-792
Author(s):  
Austin G Kulasekararaj ◽  
Alexander E Smith ◽  
Syed A Mian ◽  
Pramila Krishnamurthy ◽  
Azim M Mohamedali ◽  
...  
Keyword(s):  
High Risk ◽  
Tp53 Mutation ◽  
Practical Importance ◽  
Group Analysis ◽  
Single Mutation ◽  
Wild Type ◽  
Clone Size ◽  
Disease Evolution ◽  
Female Ratio ◽  
Tp53 Mutations

Abstract Abstract 792 Myelodysplastic syndromes are clinically and molecularly heterogeneous group of disorders with variable prognosis and propensity to leukaemic transformation. We analysed the incidence and impact of TP53 gene mutations in a large cohort of MDS patients (n=318) using next generation sequencing (454 FLX). The median age was 65 years (range 17–72 years) with a male to female ratio of 1.7:1.The median follow-up of this cohort was 18.7 months (range 1–74 months). Forty patients (12%) underwent disease modifying treatments (bone marrow transplant, intensive chemotherapy, 5-azacitidine and Lenalidomide) at the time of sample collection and hence survival analysis was censored at the date of such treatment. Twenty one (7%) has RA, MDS with isolated del 5q–26 (8%), RARS-13 (4%), RCMD/RCMD-RS-105 (32%), RAEB 1/2 −75 (24%), AML secondary to MDS-29 (9%), therapy related MDS (tMDS)-22(7%) and MDS/MPN 27 (9%). IPSS cytogenetic risk groups were; good risk-199(63%), intermediate −35 (11%) and poor risk-67 (21%) and cytogenetics failed in 17 patients (5%). The IPSS categories were, low risk: 71(24%), intermediate-1:101(32%), intermediate-2:58 (18%), high risk: 29 (9%) and 38 patients were not evaluable (proliferative CMML and MPD/MDS). Progression to AML occurred in 68 patients (20%). TP53mutations were observed in 30 (9.4%) of MDS patients. Twenty of 30 (67%) mutations were detected in int-2/high risk IPSS groups and were associated with complex cytogenetics (73%). Rest of the mutations were detected in low/int-1 IPSS patients with isolated 5q- abnormality [5 of 26, (19%)].Of the 22 cases with t MDS, 6 had TP53 mutations and 17/91 (19%) patients with RAEB and AML with trilineage dysplasia harboured TP53 mutations. Only one patient each with RCMD and MDS/MPD-U had TP53 mutation. Of the 39 mutations, 9 patients had two mutant P53 clones whereas 21 patients had single mutation. 30 of 36 (83%) mutations were located in the DNA-binding domain. Patients with therapy related MDS had increased likelihood (p<0.001) of having double mutations (5/22), while none of the patients with isolated 5q had double mutations (0/26).All except one patient (8 out of 9) with double mutations had a blast count of <10%.(p<0.001) The median clone size of TP53 mutations were 42 %( range 2.5–93%) and the median clone size of patients with double mutations was 82%.Nine patients with TP53 mutation had sequential samples tested at variable time intervals post 5-azacitidine treatment to analyze clone size and correlate with clinical responses. Four patients showed a marked decrease in clone size (24 to 3%,25:44% to 4:6%,35; 40% to 8; 17%78% to 15%,) associated with cytogenetic remission, one patient showed a increase in clone size (60% to 93%) at the time of leukaemic evolution and the remaining four patients had stable TP53 clones after 5-azacitidine. TP53 mutations strongly correlated with worse OS and PFS. The median OS for patients with wild type TP53 was not reached (NR,>66 months) compared with 9.7 months for patients with TP53 mutations (p<0.0001) and median PFS for patients with wild type TP53 was not reached (NR,>66 months) compared with 8.5 months for patients with TP53 mutations (p<0.0001). A cytogenetic sub-group analysis was performed in patients with complex cytogenetics with or without mutations of TP53, and showed patients with mutation had a worse OS (9.6 vs. 14.1 months, p<0.0001) and PFS (8.3 vs. 13.9 months, p<0.001) compared with those with wild type TP53. MDS with isolated deletion 5q harbouring a TP53 mutation(med OS 23 months) had significantly worse outcome compared with del5q patients without mutation(med OS 66 months)(p<0.002). In a multivariate analysis using co-variables: age (>55yr vs <55 yr), sex, WHO subtypes, IPSS risk category, transfusion dependency, presence or absence of mutations, TP53 was found to be the strongest predictor for OS (HR-3.78, p<0.0001, CI 2.37–6.20) and PFS (HR-3.22, p<0.0001, CI 1.97–5.26). This large single institution study confirms that TP53 mutations are an independent prognosticator of outcome in MDS. The adverse impact of TP53 persists after adjustment for cytogenetic risk and is of practical importance in evaluating the prognosis in patients with MDS. The relatively common occurrence of these mutations in different spectrums of MDS, ie isolated 5q- and complex cytogenetics, possibly implies two different mechanistic roles for p53 protein in disease evolution. Disclosures: Elebute: Alexion: Honoraria. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Very Poor Outcome and Chemoresistance of Acute Myeloid Leukemia Patients with TP53 Mutations: Correlation with Complex Karyotype and Clinical Outcome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 484-484 ◽  
Author(s):  
Cristina Papayannidis ◽  
Anna Ferrari ◽  
Stefania Paolini ◽  
Carmen Baldazzi ◽  
Chiara Sartor ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Outcome ◽  
Mutation Rate ◽  
Sanger Sequencing ◽  
Tp53 Mutation ◽  
Complex Karyotype ◽  
Wild Type ◽  
Cytogenetic Abnormalities ◽  
Tp53 Mutations ◽  
Poor Outcome

Abstract Background: AML is a heterogeneous disease. The karyotype provides important prognostic information that influences therapy and outcome. Identification of AML patients (pts) with poor prognosis such as those with complex karyotype (CK) has great interest and impact on therapeutic strategies. TP53 is the most frequently mutated gene in human tumours. TP53 mutation rate in AML was reported to be low (2.1%), but the incidence of TP53 mutations in AML with a complex aberrant karyotype is still debated. Aims: To investigate the frequency of TP53 mutations in adult AML pts, the types of mutations, the associations with recurrent cytogenetic abnormalities and their relationship with response to therapy, clinical outcome and finally their prognostic role. To this aim, we focused on a subgroup of TOT/886 AML pts treated at the Serˆgnoli Institute of Bologna between 2002 and 2013. Patients and Methods: 886 AML patients were analysed for morphology, immunophenotype, cytogenetic and for a panel of genetic alterations (FLT3, NPM1, DNMT3A, IDH1, IDH2 mutations, WT-1 expression, CBF fusion transcripts). Of these, 172 adult AML pts were also examined for TP53 mutations using several methods, including Sanger sequencing, Next-Generation Deep-Sequencing (Roche) and HiSeq 2000 (Illumina) platform. 40 samples were genotyped with Genome-Wide Human SNP 6.0 arrays or with CytoScan HD Array (Affymetrix) and analysed by Nexus Copy Numberª v7.5 (BioDiscovery). Results: Of the 886 AML patients, 172 pts were screened for TP53 mutations. Sanger sequencing analysis detected TP53 mutations in 29/172 AML patients with 36 different types of mutations; seven pts (4%) had 2 mutations. At diagnosis, the median age of TP53 mutated and wild type patients was 68 years (range 42-86), and 65 years (range 22-97) respectively. Median WBC count was 8955/mmc (range 580-74360/mmc) and 1240/mmc (range 400-238000/mmc). Conventional cytogenetics showed that: a) 52 pts (30,2%) had 3 or more chromosome abnormalities, i.e. complex karyotype; b) 71 (41,3%) presented with one or two cytogenetic abnormalities (other-AML); c) 34 pts (19,8%) had normal karyotype. Most of the TP53 mutated pts (23/29, 79.3%) had complex karyiotype, whereas only 6/29 mutated pts had “no complex Karyotype” (21% and 3% of the entire screened population, respectively). Overall, TP53 frequency was 44.2% in the complex karyotype group, suggesting a pathogenetic role of TP53 mutations in this subgroup of leukemias. As far as the types of TP53 alterations regards, the majority of mutations (32) were deleterious.. Copy Number Alterations (CNAs) analysis performed on 40 cases by Affymetrix SNP arrays showed the presence of several CNAs in all cases: they ranged from loss or gain of the full chromosome (chr) arm to focal deletions and gains targeting one or few genes involving macroscopic (>1.5 Mbps), submicroscopic genomic intervals (50 Kbps - 1.5 Mbps) and LOH (>5 Mbps) events. Of relevance, gains located on chr 8 were statistically associated with TP53 mutations (p = 0.001). In addition to the trisomy of the chr 8, others CNAs, located on chromosomes 5q, 3, 12, 17 are significantly associated (p = 0.05) with TP53 mutations. WES analysis was performed in 37 pts: 32 TP53 were wt while 5 pts were TP53 mutated. Interestingly, TP53 mutated patients had more incidence of complex karyotype, more aneuploidy state, more number of somatic mutations (median mutation rate 30/case vs 10/case, respectively). Regarding the clinical outcome, as previously reported (Grossmann V. et Al. Blood 2013), alterations of TP53 were significantly associated with poor outcome in terms of both overall survival (median survival: 4 and 31 months in TP53 mutated and wild type patients, respectively; p<0.0001) and relapse free-survival (RFS) (p < 0.0001). (Figure 1) Figure 1: Overall Survival curve of 172 AML patients with (red) or without (blue) TP53 mutations (p< 0.0001). Conclusions: Our data demonstrated that TP53 mutations are more frequent at diagnosis in the subgroup of complex karyotype AML (16.86%) (p< 0.0001–Fisher's exact test). They are mostly deleterious mutations and are significantly correlated with worst prognosis, fail to respond to therapy and rapidly progress. We recommend TP53 mutation screening at least in AML pts carrying either complex karyotype or chr. 8 gain. Supported by: ELN, AIL, AIRC, PRIN, progetto Regione-Universitˆ 2010-12 (L. Bolondi), FP7 NGS-PTL project. Disclosures No relevant conflicts of interest to declare.

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