P53 Abnormality and Prognostic Impact In Leukemia Patients with Complex Chromosomal Abnormalities

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4847-4847
Author(s):  
Xiangshan Cao ◽  
Zhaoling Zhou
Keyword(s):  
Gene Deletion ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
P53 Gene ◽  
Chromosome Abnormalities ◽  
Chromosome 17 ◽  
Prognostic Impact ◽  
Almost All ◽  
P53 Gene Deletion ◽  
Complex Chromosome

Abstract Abstract 4847 Objective: To investigate the prevalence of p53 gene deletion in leukemia patients with complex chromosome abnormalities (CCA) and their relative prognostic impact. Methods: The chromosome abnormalities in acute leukemia cases with R banding method, karyotype is named according to international nomenclature ISCN 2005. Interphase fluorescence in situ hybridization (I-FISH) determinations were performed to detect the percentage and frequency of p53 gene deletion in 38 leukemia patients with CCA and 24 patients without CCA. The rate of complete remission (CR) and median survival time (MST) were observed between the two groups in patients with CCA or without CCA. Results: (1) Complex karyotype abnormality in the leukemia patients involved in almost all of chromosomes, especially chromosome 17, chromosome 5, and chromosome 7. And the reduction of chromosome number was more common than the increase. (2) The threshold of two green and one red (2G1R) was 7%, the threshold of one green and one red (1G1R) was 4.9%. (3) The percentage of p53 gene deletion was 44.74% in CCA group and 4.16% in non-CCA group (p<0.0001). (4) p53 gene deletions were found in 9 of 10 cases with chromosome 17 abnormalities. The percentage of p53 gene deletion was achieved in 90%. (5) The CR rate was 57.14% and the MST was 31 months in patients with non-CCA compared to 11.76% CR rate and 2 months MST in patients with CCA (p<0.0001). Conclusion: The deletion of p53 gene appears to be associated with complex chromosome abnormalities and may play an important role in the prognosis of patients with leukemia Disclosures: No relevant conflicts of interest to declare.

Presence of a p53 Gene Deletion in Patients With Multiple Myeloma Predicts for Short Survival After Conventional-Dose Chemotherapy

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 802-809 ◽  
Author(s):  
Johannes Drach ◽  
Jutta Ackermann ◽  
Elke Fritz ◽  
Elisabeth Krömer ◽  
Rudolf Schuster ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Gene Deletion ◽  
P53 Gene ◽  
Induction Treatment ◽  
Structural Abnormality ◽  
Newly Diagnosed ◽  
Short Survival ◽  
Conventional Dose ◽  
P53 Gene Deletion ◽  
Conventional Dose Chemotherapy

Abstract In multiple myeloma (MM), previous studies showed that mutations of the p53 gene are rare events in patients with newly diagnosed disease, but it is not known whether deletions of p53 are of any significance in MM. To address this question, we used interphase fluorescence in situ hybridization (FISH) with a DNA probe specific for the p53 locus at 17p13 and investigated bone marrow plasma cells from 72 patients with MM (59 patients = 81.9% before therapy). By FISH, deletions of p53, which were found to be predominantly monoallelic, were detected in 32.8% and 54.5% of patients with newly diagnosed and relapsed MM, respectively. Karyotypes from six of the patients with a p53 deletion by FISH showed a structural abnormality of 17p in only one of them. Additional FISH studies including a distal-17p probe (specific for theD17S34 locus) provided evidence for an interstitial deletion on 17p resulting in loss of p53 hybridization signals in myeloma cells. Among all 59 patients with newly diagnosed MM, presence of a p53 deletion was associated with stage III (P = .054), but not with other laboratory and clinical parameters. Patients with a p53 deletion had significantly shorter survival time compared with those without a deletion, both from the time of diagnosis (median 13.9v 38.7 months; P &lt; .0001) and from the time of initiation of induction treatment consisting of conventional dose chemotherapy (median 15.9 months v median not reached at 38 months; P &lt; .0002). On stepwise multivariate regression analysis, presence of a p53 deletion was the most significant independent parameter predicting for shortened survival (P = .002). We conclude that a p53 gene deletion, which can be identified by interphase FISH in almost a third of patients with newly diagnosed MM, is a novel prognostic factor predicting for short survival of MM patients treated with conventional-dose chemotherapy. © 1998 by The American Society of Hematology.

Prognostic Impact of Ikaros (IKZF1) Gene Alterations In Childhood ALL Treated with ALL IC-BFM 2002 Protocol: A Comparison of Gene Expression and Genomic-Based Methods.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1656-1656
Author(s):  
Jana Volejnikova ◽  
Ester Mejstrikova ◽  
Karel Svojgr ◽  
Jan Stary ◽  
Jan Trka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Gene Deletion ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Induction Treatment ◽  
Prognostic Impact ◽  
Childhood All ◽  
Gene Alterations

Abstract Abstract 1656 Introduction: Recently, Ikaros (IKZF1) gene alterations were found to predict poor prognosis in childhood acute lymphoblastic leukemia (ALL). Thus, the implementation of IKZF1 status into the risk group stratification is discussed. So far, limited data are available concerning both IKZF1 importance in different treatment protocols for Ph-negative ALL and the choice of the best diagnostic method. In this study, we compared two methods based on either genomic DNA examination or gene expression analysis, and their prognostic impact within a treatment protocol for childhood ALL. Methods: Gene expression of functional (IK1, IK2) and non-DNA binding (IK4, IK6, IK8) IKZF1 isoforms was semi-quantitatively evaluated using Lab-on-a-chip (Agilent) electrophoresis and reported either as an absolute level or relatively to the total isoform signal. The thresholds for abnormal gene expression were set based on the analysis of peripheral blood (PB) of healthy donors, remission bone marrow (BM) samples of children with ALL, and sorted B- and T-cell precursor subpopulations. MLPA (multiplex ligation-dependent probe amplification) reaction including probes for Ikaros exons 1 to 8 was performed on BM DNA samples and the products were analyzed with the Coffalyser v9.4 software. Results: Results of both gene expression and MLPA analysis in the BM were available for 120 of 193 children diagnosed with ALL between 2002 and 2005. MLPA analysis revealed a deletion of at least one exon of IKZF1 gene in 17/120 (14%) patients. Of note, two patients with this deletion underwent a lineage switch (LS) from ALL to AML during the induction treatment. The entire IKZF1 gene was mononoallelically deleted in 3 patients. The ratio between non-DNA binding (IK4, IK4del, IK4A, IK6, Ik6del, IK8) and functional (IK1 and IK2) isoform expression was significantly elevated (non-DNA binding isoforms>70%) in 21 of 120 (18%) patients. The expression of a dominant-negative IK6 isoform was significantly elevated (>20% of total) in 7 of 120 (6%) patients. Surprisingly, gene deletion on one allele was not accompanied by decrease of total IKZF1 gene expression. On the contrary, patients with IKZF1 deletion had higher total IKZF1 transcript level than those without deletion (p=0.008, Mann Whitney), but it was not possible to set any reliable expression threshold for the prediction of gene deletion. The change on a DNA level was not always reflected in relative gene expression: Of 17 patients with gene deletion, only 7 had significantly altered short/long isoform ratio and 5 patients had an increased expression of IK6. Conversely, of 7 patients with IK6 overexpression, two patients had no DNA alteration, suggesting a different mechanism of altered gene expression. We next evaluated the prognostic impact of IKZF1 alterations in 113 patients treated with ALL IC-BFM 2002 protocol (5 patients were excluded due to Ph-positive ALL with imatinib-based treatment and 2 patients due to treatment change after LS). Patients with IKZF1 gene deletion had significantly worse relapse-free survival (RFS) than other patients (5-year RFS 50.0±14.4% vs. 90.8±2.9%, p=0.0002). The presence of IKZF1 deletion did not correlate with minimal residual disease (MRD) during induction treatment (days 8, 15, 33), neither in BM nor in PB. Patients with IK6 overexpression had 5-year RFS 50.0±20.4% compared to 88.4± 3.2% in those with low IK6 expression (p=0.004). The elevated short/long isoform ratio (>70%) had no prognostic impact. The best prediction of relapse was achieved via combining two factors: the presence of IKZF1 deletion detected by MLPA or the relative IK6 overexpression (>50% of total isoform signal). The 5-year RFS was 50.0±13.4% for this group (14 pts, 7 relapses) compared to 91.6±2.8% for other patients (99 pts, 8 relapses, p<0.0001). Conclusion: This study confirmed that the presence of Ikaros gene alterations was connected with a high risk of relapse also in a BFM-based protocol for Ph-negative childhood ALL treatment. The deletion within IKZF1 locus did not necessarily correlate with an altered Ikaros gene expression. Ideally, both genomic and gene expression-based approach should be applied together for the evaluation of prognosis. However, if this is not possible, the examination of DNA changes by MLPA identifies more patients who subsequently relapse than the gene expression-based approach. Support: VZ MSM 0021620813, P301/10/1877, IGA NS/10472-3 Disclosures: No relevant conflicts of interest to declare.

scholarly journals PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion

2006 ◽  
Vol 132 (2) ◽  
pp. 230-236 ◽  
Author(s):  
H. Nahi ◽  
M. Merup ◽  
S. Lehmann ◽  
S. Bengtzen ◽  
L. Mollgard ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Gene Deletion ◽  
P53 Gene ◽  
P53 Gene Deletion ◽  
Acute Myeloid

The Proportion of Clonal Plasma Cells In the Bone Marrow Analyzed by FISH Rather Than Single Chromosomal Abnormalities Predict Progression From Smoldering to Symptomatic Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2950-2950
Author(s):  
Kai Neben ◽  
Anna Jauch ◽  
Dirk Hose ◽  
Christiane Heiss ◽  
Thomas Hielscher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chromosomal Aberration ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Entire Group ◽  
P Value ◽  
Fish Analysis ◽  
Prognostic Impact

Abstract Abstract 2950 Smoldering MM (sMM) is a plasma cell disorder defined by the presence of ≥10% plasma cells in bone marrow and/or a monoclonal protein level of ≥3 g/dl in serum without organ damage. The aim of this retrospective study was to analyze whether genomic abnormalities confer prognostic information in patients with sMM who are at high risk of progression into symptomatic MM. By using fluorescent in situ hybridization (FISH), we analyzed the prognostic value of 14 chromosomal abnormalities and hyper-/non-hyperdiploidy (HD and NHD, respectively) in a series of sMM-patients (n=200). In addition, the most frequent chromosomal aberration was used to determine the percentage of clonal plasma cells (cPC) in the bone marrow. Interphase-FISH-analysis on CD138-enriched plasma cells detected gains of chromosomes 1q21 (31%), 5p15/5q35 (35%), 9q34 (45%), 11q23 (41%), 15q22 (40%), and 19q13 (41%), as well as deletions of chromosomes 8p21 (9%), 13q14 (37%) and 17p13 (7%). Furthermore, the IgH-translocations t(14;16), t(4;14), t(11;14) and IgH-translocations with unknown translocation partner were observed in a frequency of 5%, 10%, 24% and 22%, respectively. The median percentage of cPC was 85.5 (IQR: 62 – 95). For the entire group, the median follow-up time was 27.2 months (range, 18.2 – 33.5). We analyzed the prognostic impact of each chromosomal aberration on time to progression (TTP). Of all chromosomal abnormalities analyzed, only del(8p21) and the percentage of cPC showed a significant impact on TTP. The TTP at 3 years for patients with del(8p21) was 53% versus 73% for those without (p=0.01). An incremental increase of cPC in the bone marrow by 10% was associated with an elevated relative risk to develop a symptomatic MM of 33% (p<0.001). After adjustment of p-values for multiple testing, only the percentage of cPC showed a statistically significant impact on TTP (p=0.02). Our results show that FISH-analysis on CD138-enriched plasma cells is a useful technique in the study of sMM, because it allows myelomatous plasma cells to be discriminated from their normal counterparts. In addition, our findings suggest that the proportion of cPC (analyzed by FISH) rather than single chromosomal abnormalities predict progression from sMM to symptomatic MM. FISH-based information can be obtained easily at the time of diagnosis, which would help to establish an individually adapted follow-up strategy. Aberration yes vs. no N Incidence 3-yr TTP (present vs. absent) Hazard ratio Wald test p-value adjusted del(8p21) 190 9% 53% vs. 73% 2.59 0.1 del(13q14) 200 37% 61% vs. 79% 1.77 0.8 del(17p13) 198 7% 56% vs. 72% 1.95 1 t (4;14) 198 10% 52% vs. 73% 1.68 1 t (11;14) 198 24% 77% vs. 69% 0.51 1 t (14;16) 197 5% 57% vs. 71% 1.59 1 +1q21 197 31% 60% vs. 75% 1.71 1 HD vs. NHD 197 40% 65% vs. 74% 1.67 1 10% increase of cPC 200 – – 1.33 0.02 cPC >95 vs. ≤95% 200 23% vs. 77% 46% vs. 80% 3.84 <0.001 Disclosures: No relevant conflicts of interest to declare.

Genetic Characterization of Patients with Monoallelic and Biallelic CEBPA Mutations Using a Targeted Sequencing Approach Reveals Differences in the Spectrum of Cooperating Mutations

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2385-2385
Author(s):  
Nikola P Konstandin ◽  
Klaus H. Metzeler ◽  
Annika Dufour ◽  
Philipp A Greif ◽  
Tobias Herold ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Strong Association ◽  
Amplicon Sequencing ◽  
Multicenter Trial ◽  
Prognostic Impact ◽  
Enhancer Binding Protein ◽  
Frequent Mutations ◽  
Cebpa Mutations ◽  
Biallelic Mutations ◽  
Almost All

Abstract Mutations in the CCAAT/enhancer binding protein alpha (CEBPA) are detected in about 10% of patients with cytogenetically normal acute myeloid leukemia (CN-AML). CEBPA mutation can either affect both CEBPA alleles (biallelic, biCEBPA) or only one allele (monoallelic, moCEBPA). We and others have shown that only patients with biCEBPA mutations have favorable outcomes when compared to other CN-AML patients (Dufour et al, JCO 2009; Green et al, JCO, 2010). Interestingly, biCEBPA mutations are rarely associated with other known prognostic mutations (e.g. FLT3-ITD, NPM1). In this study we aimed to characterize the mutational spectrum of CN-AML patients with mo- and biCEBPA mutations using a targeted amplicon sequencing approach. We analyzed 45 biCEBPA patients and 35 moCEBPA patients. 55 of these patients (26 biCEBPA and 29 moCEBPA) were enrolled in a multicenter trial of the German AML Cooperative Group (AMLCG-1999). Our amplicon resequencing panel included 42 genes which are known to be frequently mutated in AML (Haloplex, target region 62 kilobases). Out of these 42 genes we identified 23 different mutated genes in the biCEBPA subgroup and a total of 28 different mutated genes in the moCEBPA cohort. The mean number of mutated genes per moCEBPA patient was significantly larger (4.37±1.6) than in biCEBPA patients (2.96±1.22) (P<0.05). The two groups also differed remarkably with regard to the genes that were mutated. In the moCEBPA group FLT3 (46%), NPM1 (46%), TET2 (37%) and DNMT3A (26%) were the most frequently mutated genes, whereas the biCEBPA group showed frequent mutations in TET2 (40%), GATA2 (36%) and FLT3 (18%). Thus there was a strong association of NPM1 (P<0.0001), FLT3 (P=0.01) and IDH2 (P=0.04) mutations with the moCEBPA group. GATA2 mutations were significantly associated with biCEBPA mutations (P=0.0003). NPM1 and biCEBPA mutations were mutually exclusive. In this large and well characterized CEBPA-mutated patient cohort we identified distinct mutational landscapes in patients with moCEBPA and biCEBPA mutated CN-AML. The lower number of mutated genes within the biCEBPA group suggests that biallelic CEBPA mutations may act as a strong driver. In almost all cases, patients with biallelic mutations of CEBPA have a C-terminal mutation in one allele of CEBPA and an N-terminal mutation in the other allele. These date provide further insight into the genetic background of CEBPA mutated CN-AML. We are currently analyzing the prognostic impact of the associated mutations. Disclosures No relevant conflicts of interest to declare.

p53 gene deletion and trisomy 12 in hairy cell leukemia and its variant

1999 ◽  
Vol 23 (11) ◽  
pp. 1041-1045 ◽  
Author(s):  
Kalliopi Vallianatou ◽  
Vasantha Brito-Babapulle ◽  
Estela Matutes ◽  
Shayne Atkinson ◽  
Daniel Catovsky
Keyword(s):  
Hairy Cell Leukemia ◽  
Gene Deletion ◽  
P53 Gene ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Trisomy 12 ◽  
P53 Gene Deletion

scholarly journals Detection of p 16, RB, CDK4, and p53 Gene Deletion and Amplification by Fluorescence In Situ Hybridization in 96 Gliomas

1999 ◽  
Vol 112 (6) ◽  
pp. 801-809 ◽  
Author(s):  
Arie Perry ◽  
Kari Anderl ◽  
Tom J. Borell ◽  
David W. Kimmel ◽  
Chiao H. Wang ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Gene Deletion ◽  
P53 Gene ◽  
P 16 ◽  
P53 Gene Deletion

Multicolor Fluorescence In Situ Hybridization (M-FISH) in Highly Aggressive B-Cell Lymphomas with 8q24/MYC Involvement Revealed the Heterogeneity of 13q Abnormalities with Unexpected Partial Gains.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2068-2068
Author(s):  
Violaine Havelange ◽  
Geneviève Ameye ◽  
Evelyne Callet-Bauchu ◽  
Nicole Dastugue ◽  
Carole Barin ◽  
...  
Keyword(s):  
B Cell ◽  
Chromosomal Abnormalities ◽  
Chromosomal Rearrangements ◽  
Chromosome 17 ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
B Cell Lymphomas ◽  
Chromosomal Alterations ◽  
Myc Oncogene ◽  
Additional Chromosomal Abnormalities

Abstract Chromosomal translocations involving the MYC oncogene (8q24) are known to occur in Burkitt lymphomas/leukemias (BL) but also in 5–30% of diffuse large B-cell lymphomas which are usually highly aggressive (8q24 DLBCL). Two recent conventional cytogenetics (CC) studies showed that secondary chromosomal abnormalities have a negative prognostic impact, especially13q abnormalities (frequently described as a deletion and usually associated with a complex karyotype, i.e. > 3 chromosomal alterations), mainly in childhood mature B-cell lymphomas, and in a less extent 7q, 3q, 22q and chromosome 17. M-FISH was applied to 120 (74% adults and 26% children) high grade B-cell non-Hodgkin lymphomas (86% BL, 14% 8q24 DLBCL) carrying MYC rearrangement and complex karyotype and/or 13q abnormality in order to find recurrent and/or cryptic chromosomal alterations. Abnormal metaphases were available in 96 (80%) cases. We described ‘new’ (not seen in CC) chromosomal rearrangements in 50 (52%) cases, refined those seen by CC in 28 (29%) cases and confirmed CC abnormalities in 18 (19%) cases. M-FISH allowed to characterize 55 structural 13q abnormalities in 42 patients (21 ‘new’ alterations): 24 der(13q) leading to partial del(13q) and partial gain of different partner chromosomes [mainly 1q or 7q], 15 del(13q) [of 2 minimal regions : q14 & q31q34], 13 gains (only 2 seen by CC) and 3 balanced translocations. Combined results of CC and M-FISH showed that the most frequent abnormalities among patients with complex karyotype involved 1q, 7q, Xq, 3q, 18q, 6q, 17p and chromosome 22 (excluding 8q24 translocations). 79 1q abnormalities were detected in 54 patients (26 % ‘new’): mostly gains (minimal amplified region: q22q31) due to unbalanced translocations with chromosomes 13, 22, 7 (59%) or duplications (25%). 55 partial 7q gains were observed in 42 patients (22% ‘new’), mostly +7 or unbalanced translocations with 13q, 6q or 1q. The other most common abnormalities were: t(14;18) in 8q24 DLBCL, del(6q), der(3q) with various partners leading to partial loss of 3q, monosomy 17 or del(17p) and numerical changes of chromosomes 22 (monosomy) and X. In conclusion, this study confirms the contribution of M-FISH in refining CC results in highly aggressive 8q24 B-cell lymphomas: ‘new’ rearrangements were identified especially in 1q (leading to partial 1q gains), 18q, 6q (leading to partial 6q deletions), 13q ; partial 13q gains were underestimated by CC and both 13q deletions and gains were more heterogeneous than expected. We are characterizing these prognostic additional chromosomal abnormalities with SNP-CHIPS 50K array (Affymetrix) to look for candidate genes and/or cellular pathways involved in Burkitt lymphomagenesis in cooperation with oncogenic effect of MYC. °on behalf of the GFCH (Groupe Francophone de Cytogénétique Hématologique) and the BCG-Ho (Belgian Cytogenetic Group of Hematology and Oncology).

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