Incidence and Prognostic Value of TP53 Mutations in Lower Risk MDS with Del 5q.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2809-2809
Author(s):  
Cecile Bally ◽  
Lionel Ades ◽  
Aline Renneville ◽  
Sophie Raynaud ◽  
Virginie Eclache ◽  
...  
Keyword(s):  
Early Phase ◽  
Lower Risk ◽  
Prognostic Value ◽  
Tp53 Mutation ◽  
Cytogenetic Response ◽  
Complex Karyotype ◽  
Early Disease ◽  
Tp53 Mutations ◽  
Erythroid Response ◽  
Significant Difference

Abstract Abstract 2809 Background: TP53 gene mutations, frequent in AML and MDS with complex karyotype, have recently been found in about 20% of lower risk MDS with del 5q, where they possibly conferred resistance to lenalidomide (LEN), and a higher risk of AML progression (Jadersten, JCO, 2011). We assessed the incidence and prognostic value of TP53 mutations in 79 lower risk MDS with del 5q, treated or not with LEN, and analysed in early disease phase or after progression to higher risk MDS or AML. Methods: IPSS low and int 1 (Lower) risk MDS with del 5q were analysed at diagnosis or onset of LEN (“early phase”) and/or after progression to IPSS high or int 2 (higher) risk MDS or AML. LEN was administered at 5 or 10 mg/d during 16 weeks, and continued in erythroid responders until relapse or disease progression. TP53 mutations were detected by the functional FASAY technique, assessing the transcriptional activity of p53 by co-transfecting an open gap repair plasmid with the product of amplification of TP53 from patients in yeasts whose growth is dependent on p53 functionality. The detection limit of this technique is around 10–15% (Flaman, PNAS 1995). Mutations found by FASAY were confirmed by direct sequencing, using Sanger method and /or (more recently) high sensitivity (1%) Next Generation Sequencing (NGS) by pyrosequencing (GS Junior System-Roche, with the IRON II plate design). Results: 79 lower risk MDS with del 5q from 6 French centers of the GFM were analyzed, including 62 at diagnosis or onset of LEN (“early phase”), and 17 after progression to higher risk MDS or AML (5 of the latter were also retrospectively analysed on early phase samples). Overall, 28 (35%) of the 79 patients had TP53 mutation, including 16 (26%) of the 62 pts analyzed at early phase and 12 (70%) of the 17 evaluated after higher risk MDS or AML progression (p= 0.001). The 62 early phase pts had marrow blasts <5% and 5–9% in 91 and 9% of the cases, isolated del 5q, del 5q+1 and del5q+>1 (complex karyotype) in 84, 14 and 2% of the cases, and IPSS low and int 1 in 80 and 20% of the cases, respectively. No significant difference was found between mutated and non mutated cases for baseline characteristics including gender, age, WHO classification, cytogenetic complexity and IPSS. In the 5 pts analysed after progression where early phase samples were available, who all had received LEN, 4 had TP53 mutation at progression. In all of them, TP53 mutation was already detectable during early phase. However, the percentage of mutated colonies found by FASAY increased with progression, from 18 to 75%, 26 to 55%, 12 to 87% and 13 to 23%, respectively, showing an increase of the size of the mutated clone at progression. Among the 43 pts analyzed in early phase who received LEN (we excluded the 5 pts analysed after progression where early phase samples were available, to avoid bias), 36 (84 %) had isolated del 5q, 6 (14%) del 5q+1, and 1 (2%) had complex karyotype. IPSS was low in 73% and int-1 in 27%. 12/43 (28%) had TP53 mutation. 63% of the 43 pts achieved erythroid response, and 9 (47%) of the 19 pts evaluable at erythroid response achieved cytogenetic response. Erythroid response was seen in 45% mutated vs 71% non mutated cases (p= 0.258). Cytogenetic response was seen in 1/8(12%) mutated vs 8/11 (73%) non mutated cases (p=0.020). In those 43 pts who received LEN, the cumulative incidence (CI) of AML evolution, with death as a competitive event, did not significantly differ between patients with or without TP53 mutation (3 year CI of 35% vs 30%, p=0.33). Finally, in those pts, TP53 mutational status had no significant impact on OS (median 49 months in mutated pts vs not reached in non mutated pts, p=0.48, figure 1). Conclusion: We confirm the presence of TP53 mutations in about 25 % of lower risk MDS with del 5q analysed in early disease phase. TP53 mutations, in those patients, were not correlated with other baseline parameters. When treated with LEN, mutated cases had similar hematological response, lower cytogenetic response but no significant difference in progression to higher risk MDS or AML and survival compared to non mutated cases. The high incidence of TP 53 mutations at progression to higher risk MDS/AML (70%), and the increase in the TP53 mutated clone size observed during progression in pts with a baseline mutation support the pathophysiological importance of TP53 mutations in disease progression in lower risk MDS with del 5q. Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance Of TP53 mutations and Single Nucleotide Polymorphisms In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4971-4971
Author(s):  
Simon B. Zeichner ◽  
Sarah Alghamdi ◽  
Gina Elhammady ◽  
Robert Poppiti ◽  
Amilcar Castellano-Sanchez
Keyword(s):  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Performance Status ◽  
Nucleotide Polymorphisms ◽  
Complex Karyotype ◽  
Single Nucleotide ◽  
Tp53 Mutations ◽  
Significant Difference ◽  
De Novo Aml

Abstract Background The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median OS ranging from several months to more than 10 years. Age at diagnosis, performance status (PS), and karyotype expression have long been established in prognostication. Loss of TP53, a tumor suppressor gene located on the short arm of chromosome 17, is one of the most frequent genetic abnormalities in human cancer and is one of the more promising prognostic markers for AML. Studies have shown that TP53 mutations are present in 5-25% of all AML patients, in 70% of those with complex karyotypes, and are associated with old age, chemotherapy resistance, and worse OS. Single nucleotide polymorphisms (SNPs), changes in DNA seen in an appreciable amount of the population, have been examined in AML and studies have suggested a possible correlation with worse outcomes. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized TP53 mutations and SNPs would mimic the literature, occurring in a minority of patients, and conferring a worse OS. Methods We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n =10). Immunohistochemical (IHC) analysis of bone marrows and peripheral blood smears was assessed via DO-1 antibody on paraffin embedded tissue. Conventional cytogenetic analyses were performed on short-term cultured bone marrow and peripheral blood cells with the use of the GTG-banding technique. TP53 PCR sequencing was performed using DNA from bone marrow smears using the Sanger sequencing platform and resolved by capillary electrophoresis. Analysis was performed using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. Descriptive frequencies and median survivals were calculated for demographic information, prognostic factors, and treatment variables. A univariate analysis was performed. Results The majority of patients in our pilot study were older than age 60 (80%), male (60%), Hispanic (60%), and had a poor PS (ECOG 2-3: 60%). Most patients had de-novo AML (50%) with an intermediate (50%) non-complex (70%) karyotype and a TP53 P72R SNP (50%). Fewer than half of these patients harbored TP53 mutations (40%). There was no significant difference in OS based on sex, AML history, risk-stratified karyotype, or TP53 mutation. There was a trend toward improved survival among patients younger than age 60 (11, 4 mo, p = 0.09), of Hispanic ethnicity (8, 1 mo, p = 0.11), and those not harboring P72R (8, 2, p = 0.10). There was a significant improvement in survival among patients with a better PS (28, 4 mo, p = 0.01) and those who did not have a complex karyotype (8, 1 mo, p = 0.03). Among patients with a TP53-mutation, there were a larger number of individuals who were younger than age 60 (25.0, 16.7%), who were male (75.0, 50.0%), had a good performance status (ECOG 0-1: 50.0, 16.7%), had de-novo AML (50.0, 66.7%), and who had an adverse karyotype (50.0, 33%). Patients with a P72R SNP were more often male (80, 40%) and had a worse PS (ECOG 2-3: 80, 40%) with AML secondary to MDS (60, 20%) and a complex karyotype (40, 0%). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). Patients with more than one TP53 mutation had a worse clinical course than those with only a single mutation. Conclusion Our study demonstrated that poor PS and the presence of a complex karyotype were associated with a decreased OS. TP53 mutations were relatively uncommon, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a trend toward worse OS among patients with a specific SNP. These results suggest that different TP53 mutations and SNPs should not be treated the same, and that some may confer a worse prognosis than others. Larger studies are needed to validate these findings. Disclosures: No relevant conflicts of interest to declare.

In CLL with Complex Aberrant Karyotype Distinct Entities Can Be Deciphered by Molecular Genetic and Cytogenetic Parameters

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3138-3138 ◽  
Author(s):  
Frank Dicker ◽  
Susanne Schnittger ◽  
Torsten Haferlach ◽  
Wolfgang Kern ◽  
Claudia Haferlach
Keyword(s):  
High Risk ◽  
Lower Risk ◽  
Tp53 Mutation ◽  
Risk Group ◽  
Molecular Genetic ◽  
Tp53 Gene ◽  
High Risk Group ◽  
Complex Karyotype ◽  
Tp53 Mutations ◽  
The Poor

Abstract Metaphase cytogenetics have recently defined important prognostic subgroups in CLL. In addition to the poor prognosis FISH markers del(17p) and del(11q), the presence of translocations and a complex aberrant karyotype, defined by chromosome banding analyses, have been associated with shorter overall survival in a retrospective analysis. Thus far, a complex aberrant karyotype is defined by a number of three or more chromosomal aberrations, therefore, we aimed at characterizing an unselected CLL cohort of 92 patients with complex aberrant karyotype in more detail with molecular genetic, cytogenetic, and immunophenotypic parameters. Median age at diagnosis was 62.5 years (range: 33.4–83.3 years), the male/female ratio was 2.8. An unmutated IgVH status (&lt;= 2% mutations) was detected in 51 (60.7%) of 84 analyzed samples. A positive CD38 expression (&gt;= 30% CD38 positive cells) was detected in 55 (64%) of 86 samples and TP53 gene mutations by denaturing high performance liquid chromatography of exons 4–9 of TP53 in 29 (36.7%) of 79 samples. As the main approach for prognostication in CLL uses FISH for del(17p), del(11q), +12, del(13q) sole and normal, we related our cohort with complex aberrant karyotype into these different FISH categories. The poor prognosis markers del(17p) and del(11q) were detected with frequencies of 39.1% (n=36) and 22.8% (n=21), respectively, accounting for almost two third of all samples (n=57, 61.9%). An overlap between del(17p) and del(11q) was detected in 5 of the 36 del(17p) cases. The intermediate risk FISH marker +12 and low risk FISH markers del(13q) as sole abnormality and “normal karyotype” appeared with an incidence of 8.7% (n=8), 21.7% (n=20) and 7.6% (n=7), respectively. The high incidence of del(11q) and del(17p) in complex karyotype seems likely, as genes implicated in sensing DNA damage and in regulating apoptosis, ATM and TP53, are candidate genes in these deleted regions. As TP53 mutations have been suggested as independent poor prognostic markers, we also added TP53 gene mutation analysis to the FISH stratification. Del(17p) was associated with TP53 mutation in 26 (86.7%) of 30 analyzed cases, whereas the three residual TP53 mutations were associated with del(11q) (n=1) and del(13q) as sole abnormality (n=2). Therefore, we chose to merge samples with high risk features within the complex karyotype into one group (n=59), i.e., samples with del(17p), del(11q) or TP53 mutation, and compared these samples to the remaining samples (n=33). Effectively, the high risk group compared to the other cohort was significantly associated with an unmutated IgVH (p=0.02, Fisher’s exact test) and with an increased, median amount of cytogenetic aberrations (4.9 vs. 3.7 aberrations, p=0.005, t-test). However, no significant difference between the two groups regarding a CD38 positive status was detected (p=0.257). The prognostic impact of high risk features (del(17p), del(11q) and TP53 mutation) within the group defined above vs the lower risk group was analyzed with log-rank statistics with respect to time from diagnosis of CLL to initial treatment (TTT). 34 patients from the high risk group and 18 patients from the low risk group were available for analysis. The high risk features within the complex karyotype were significantly associated with a higher risk of early treatment in log-rank statistics with a median TTT of 12.2 month in the higher risk group compared to 70.1 month in the lower risk group (p=0.005). In conclusion, based on poor risk cytogenetic and molecular genetic features within the group of CLL with complex aberrant karyotype, we characterized patients with a higher risk of early treatment initiation. This group includes samples with del(17p), del(11q) and TP53 mutations.

Prognostic Value of TP53 Gene Mutations in Higher Risk MDS Treated with Azacitidine

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1706-1706
Author(s):  
Cecile Bally ◽  
Lionel Ades ◽  
Aline Renneville ◽  
Claude Preudhomme ◽  
Marie-Joelle Mozziconacci ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Value ◽  
Tp53 Mutation ◽  
Conflicts Of Interest ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Chromosome 17 ◽  
Complex Karyotype ◽  
Tp53 Mutations ◽  
Tp53 Gene Mutations

Abstract Abstract 1706 Background: TP53 gene mutations in MDS and AML are, with the exception of cases of isolated del 5q, generally associated with complex karyotype, often including del (17p) (with loss of the remaining TP53 allele) and with poor overall outcome (Fenaux, BJH, 1992; Bejar, NEJM, 2011). They are, in MDS and AML, more specifically generally associated with resistance to chemotherapy, including anthracycline-Ara C combinations and low-dose AraC (Wattel, Blood, 1994), but their correlation with treatment outcome with hypomethylating agents has not been studied. Our aim was to assess the prognostic value of TP53 mutations for response to Azacitidine (AZA) in higher risk MDS, AML with 20–30% blasts or advanced CMML (corresponding to the EU label for AZA). Methods: Patients were treated with AZA (75 mg/m2/d, generally during 7 days every 4 weeks) in 2 centers of the Groupe Francophone des Myélodysplasies. TP53 mutations were detected by the functional FASAY technique, which assesses the transcriptional activity of p53 by co-transfecting an open gap repair plasmid with the product of amplification of TP53 from patients in yeasts whose growth is dependent on the functionality of p53. The detection limit of this technique is around 10–15% (Flaman et al, PNAS 1995). The presence of mutations was subsequently confirmed by direct sequencing using the Sanger method and, more recently, by a Next-Generation Sequencing (NGS) assay using pyrosequencing (GS Junior System, Roche with the IRON II plate design). Results: 72 pts treated with AZA (median n° of cycles of AZA received 4, range 1–7) were analyzed, including 34 MDS according to WHO classification (IPSS high: 9, int2: 13, int1: 6, undetermined: 6), 33 AML with 20–30% blasts and 5 advanced CMML. According to IPSS, karyotype was favorable in 27%, intermediate in 13% and unfavorable in 60% of the pts, including 47% of complex karyotypes. Response to AZA (according to IWG 2006 criteria) was observed overall in 51% of the pts, including 34% CR, 6% PR, 4% marrow CR, 7% stable disease with HI. Median overall survival (OS) from onset of AZA was 15.6 months, possibly explained by the 47% of complex karyotypes. 29 (40%) patients had a TP53 mutation, detected by FASAY technique and subsequently confirmed by Sanger sequencing or NGS (no false positive with FASAY technique was observed). 22 of the 34 (67%) patients with complex karyotype had a TP53 mutation. In the 7 patients with TP53 mutation without complex karyotype, 3 pts had isolated del(5q), 2 had del (17p) (isolated in 1 pt, with del (20q) in 1 pt), 1 had pentasomy 11 and 1 had +8, del(20q). Ten (77%) of the 13 cases with chromosome 17 rearrangement leading to del (17p) were TP53 mutated. Overall Response to AZA (41% vs 57%, p= 0.227) and CR rate (21% vs 42%, p= 0.073) did not significantly differ between TP53 mutated and wild-type patients. Nevertheless, OS was negatively influenced by the presence of TP53 mutation (median 13 vs 21 months, p= 0.0022, figure 1), complex cytogenetics (median 14 vs 18 months, p=0.0120), WHO AML diagnosis (median 13 vs 21 months for WHO-MDS or CMML, p= 0.0014). By multivariate analysis, marrow blast % (HR 1.03 (1.01–1.05) (p<10-4)) and TP53 mutational status (HR 2.29 (1.06–4.97) p=0.035) were the only 2 factors retaining statistical significance for OS. When the analysis was restricted to WHO MDS and CMML patients, only the presence of TP53 mutation was associated with worse OS in multivariate analysis (HR=4.08 (1.31– 12.7), p=0.015)). Conclusion: In higher risk MDS (and AML with 20–30% blasts and advanced CMML) patients treated with AZA, the presence of TP53 mutation appears to constitute an independent prognostic parameter of poorer survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dynamic Telomere Shortening and Chromosomal Instability in Irradiated CD34+ Cells Transduced with TP53 Hotspot Mutations R175H, R248W and R249S

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4832-4832
Author(s):  
Azam Salari ◽  
Kathrin Thomay ◽  
Andrea Schienke ◽  
Maike Hagedorn ◽  
Juliane Ebersold ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Tp53 Mutation ◽  
Lower Amount ◽  
Complex Karyotype ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Tp53 Mutations ◽  
Ht1080 Cells ◽  
Stem And Progenitor Cells ◽  
Hotspot Mutations

Abstract Patients with MDS and a complex karyotype have a very short median survival and a high risk of transformation into AML. We showed earlier that TP53 mutations are associated with complex karyotype and disease progression. However, it is poorly understood how TP53 mutations contribute to the induction of chromosomal instability in hematopoietic stem and progenitor cells. We therefore established a long-term cell culture (LTC) model and investigated the role of TP53 in human CD34+ hematopoietic stem and progenitor cells (HSCs) isolated from cord blood and in HT1080 cells over 6 weeks. We chose 3 different modifications: 1) TP53-deficient HSCs via shRNA knockdown, 2) HSCs with different lentivirally introduced TP53 hotspot mutations (R248W, R175H, R273H, R249S) and 3) HT1080 cells with different lentivirally introduced TP53 hotspot mutations (R248W, R175H, R273H, R249S). We performed each LTC at least three times. In order to stress the cells and induce chromosomal instability, we irradiated half of the cells. Besides functional assays in the first week, we performed detailed cytogenetic analysis including telomere length measurement at weeks 1, 3 and 6. TP53 mutations and the downregulation of TP53 led to impaired hematopoiesis with decreased erythroid differentiation, increased apoptosis and decreased proliferation. None of the modifications induced chromosomal instability in cells without irradiation. In the irradiated cells, all cells carrying a TP53 mutation or a TP53 downregulation developed a chromosomal instability in comparison to the cells transduced with control vectors. However, no stable complex clones developed. Telomeres shortened during follow-up in HSCs carrying the mutations R175H, R248W and R249S. No other cells showed a dynamic response in telomere length. In order to analyze the DNA repair capacity, we performed yH2AX foci assay. Surprisingly, the same cells which showed a telomere shortening showed a lower amount of foci. This could be due to a lower amount of double-strand breaks or to a lower ability to form foci. In summary, TP53 mutations and the downregulation of TP53 led to an increased chromosomal instability in irradiated cells only. Modifications alone did not lead to the development of complex karyotypes. Furthermore, only the mutations R175H, R248W and R249S led to a telomere shortening. In conclusion, a TP53 mutation seems to require additional passenger mutations in order to lead to MDS or AML with complex karyotype. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals TP53 Allelic Status in Myeloid Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4458-4458
Author(s):  
Xinjie Xu ◽  
Christian Paxton ◽  
Kristin H. Karner
Keyword(s):  
Older Patients ◽  
Tp53 Mutation ◽  
Karyotype Analysis ◽  
Dominant Negative Effect ◽  
Molecular Testing ◽  
Study Cohort ◽  
Complex Karyotype ◽  
Tp53 Mutations ◽  
Myeloid Malignancies ◽  
Allelic Status

Abstract Introduction TP53 is a tumor suppressor gene involved in regulating cell division and apoptosis in response to DNA damage. In hematologic malignancies, TP53 alterations are present in both myeloid and lymphoid malignancies. TP53 alterations including both sequence level mutations and deletions occur in 8-10% of de novo acute myeloid leukemia (AML), and are significantly enriched in patients with therapy-related myeloid neoplasms with a frequency of 25-40%. TP53 alterations are associated with complex karyotype, resistance to traditional cytotoxic chemotherapy and dismal outcome, and are well established poor prognostic markers for both AML and myelodysplastic syndrome (MDS). While both biallelic and monoallelic TP53 alterations are seen, biallelic TP53 alteration is more frequent in both AML and MDS. In the instances of monoallelic TP53 alterations, the remaining wild-type allele can be inhibited by the dominant negative effect of the mutant p53. The clinical implication of TP53 allelic status remains controversial. Biallelic TP53 alterations and/or high TP53 mutation variant allele frequency (VAF) are associated with older patients, complex karyotype, few co-occurring mutations and poor outcome in both AML and MDS. Other studies demonstrate that biallelic vs. monoallelic TP53 alterations or high vs. low TP53 VAF have similar prognosis in myeloid malignancies. Current European LeukemiaNet (ELN) recommends testing TP53 deletion using karyotype analysis and TP53 mutations by molecular testing. Methods: We performed a retrospective review of patients with myeloid malignancies, myeloid next generation sequencing (NGS) panel and cytogenetic tests performed at ARUP Laboratories. We identified 18 patients with myeloid malignancies and TP53 mutations. We used a combination of karyotype analysis, FISH, chromosomal microarray (CMA) and NGS to determine the TP53 allelic status. Results: 18 patients diagnosed with myeloid malignancies and TP53 mutations were identified. Among them, 6 were diagnosed with AML, 10 had MDS, one with CMML and one had post essential thrombocythemia myelofibrosis. Age range is from 31 to 78 with a median age 65.5 years. 23 TP53 mutations were identified among 18 patients. The majority (78%) of TP53 mutations are located in the DNA binding domain. Co-occurring mutations are uncommon in patients with TP53 mutations. 11 out of 18 patients did not have co-occurring mutations in other myeloid malignancy related genes. Three cases had 1, three cases had 2, and one case had 3 co-occurring mutations at the time of diagnosis. Karyotype analysis and FISH were performed on all 18 patients. CMA was performed on 9 patients. 17p abnormalities, defined by the deletion or copy-neutral loss of heterozygosity (CN-LOH) of 17p, were seen in 9 out of 18 cases. The 17p abnormalities in 8 out of these 9 cases were visible by karyotype. Case 11 had a CN-LOH identified by CMA which was cryptic by karyotype. Typical complex karyotype was seen in 16 out of 18 cases. Biallelic TP53 alterations are defined by either the presence of a TP53 mutation with a 17p abnormality (deletion or CN-LOH), or two TP53 mutations with similar VAF, or one TP53 mutation with VAF &gt;50%. Biallelic TP53 alterations were seen more frequently compared with monoallelic TP53 alterations (14 vs. 4 patients) and enriched in older patients (Figure 1). All 6 AML patients had biallelic TP53 alterations. Outcome data is available in 10 patients including 8 patients with biallelic and 2 patients with monoallelic TP53 alterations. Patients with biallelic TP53 alterations have dismal outcome (Figure 2). Patient 7 represents an atypical patient with TP53 alteration in our study cohort. She was diagnosed with MDS at the age of 31. She had monoallelic TP53 mutation with a relatively low VAF and normal karyotype through her disease course. Her MDS never progressed and she remained in remission after transplant for more than four years and still doing well. Conclusion: In this study, we evaluated the TP53 allelic status in 18 patients with myeloid malignancies. Biallelic TP53 alterations are more frequent than monoallelic TP53 alterations, and are associated with older patients, and fewer co-occurring mutations. Biallelic TP53 alterations are associated with typical complex karyotype and dismal outcome. Our study supports the importance to differentiate between biallelic and monoallelic TP53 alterations. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

Leukemia Associated TP53 Mutations in AML Patients ARE Strongly Associated with Complex Karyotype and Poor Outcome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2379-2379 ◽  
Author(s):  
Anna Ferrari ◽  
Cristina Papayannidis ◽  
Carmen Baldazzi ◽  
Ilaria Iacobucci ◽  
Stefania Paolini ◽  
...  
Keyword(s):  
Copy Number ◽  
Sanger Sequencing ◽  
Tp53 Mutation ◽  
Genetic Alterations ◽  
Chromosome Abnormalities ◽  
Chromosome 8 ◽  
Complex Karyotype ◽  
Cytogenetic Abnormalities ◽  
Tp53 Mutations ◽  
Poor Outcome

Abstract Background: AML is a heterogeneous disease with various chromosomal aberrations. The karyotype at diagnosis provides important prognostic information that influences therapy and outcome, and patients (pts) with complex karyotype (CK) have generally a poor outcome. TP53 is the most frequently mutated gene in human tumors. The reported TP53 mutation rate in AML is low (2.1%). In contrast, the incidence of TP53 mutations in AML with a complex aberrant karyotype is higher (69-78%). Aims: To investigate the frequency, the types of mutations, the associated cytogenetic abnormalities and the prognostic role of TP53 mutations in adult AML pts, we focused the screening on subgroups of AML with chromosome abnormalities. Patients and Methods: 886 AML patients were analysed at the Seràgnoli Institute of Bologna between 2002 and 2013 for morphology, immunophenotype, cytogenetic and for a panel of genetic alterations (FLT3, NPM, WT1, CBF fusion transcripts, DNMT3A, IDH1, IDH2, etc). 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 (35/172 pts). 40 samples were genotyped with Genome-Wide Human SNP 6.0 arrays or with CytoScan HD Array (Affymetrix) and analysed by Nexus Copy Number™ v7.5 (BioDiscovery). Results: Of the 886 AML patients beforehand analysed, 172 pts were screened for TP53 mutations and were correlated with cytogenetic analysis (excluding 15 pts where the karyotype was not available). 1. Fifty-two pts (30,2%) have 3 or more chromosome abnormalities, i.e. complex karyotype; 2. 71 (41,3%) presented one or two cytogenetic abnormalities (other-AML) and 3. 34 pts (19,8%) have normal karyotype. Sanger sequencing analysis detected TP53 mutations on 29 patients with 36 different types of mutations; seven pts (4%) have 2 mutations. Mostly (23/29) of the TP53 mutated pts (79.3%) had complex karyotype while only 6/29 mutated pts have “no CK” (21% and 3% of the entire screened population). Overall, between pts with complex karyotype, TP53 frequency is 44.2%. Regarding the types of the TP53 alterations, 32 were deleterious point mutations (http://p53.iarc.fr/TP53GeneVariations.aspx) and 4 deletions. Forty pts were also analysed for Copy Number Alterations (CNAs) by Affymetrix SNP arrays: several CNAs were found ranged from loss or gain of complete chromosome (chr) arms 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). Seven genes are included in these regions (RGS20, TCEA1, LINC01299, ARMC1, MTFR1, RAD54B, KIAA1429). In addition to the trisomy of the chr 8, others CNAs, located on other chromosomes are significantly associated (p = 0.05) with TP53 mutations: loss of chr 5q, chr 3 (p22.3), chr 12 (p12.3) and the gain of chr 17 (p11.2), chr 16 (p11.2-11.3) and chr 14 (q32.33). The zinc finger gene ZNF705B, implicated in the regulation of transcription was the most differentially associated gene (gain). WES analysis was done in 37 pts, 32 TP53 were wt while 5 pts were TP53 mutated: of importance, CDC27, PLIN4 and MUC4 were found also mutated in 3 out of 5 TP53 mutated (60%). Clinical outcome: as previously reported, alterations of TP53 were significantly associated with poor outcome in terms of both overall survival and disease free-survival (P < 0.0001). Conclusions: Our data demonstrated that TP53 mutations occur in 16.86% of AML with a higher frequency in the subgroup of complex karyotype AML (p< 0.0001–Fischer’s exact test). Since TP53 mutations have predicted to be deleterious and significantly correlated with prognosis, TP53 mutation screening should be recommended at least in complex karyotype AML pts. Furthermore, although further studies in larger numbers of patients are needed, the gain of chromosome 8 was observed to be significantly associated to TP53 mutations pts. Supported by: ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project. Disclosures Martinelli: Novartis: Speakers Bureau; Bristol Mayers Squibb: Speakers Bureau; Pfizer: Speakers Bureau.

Detection of TP53 Mutations in Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). a Comparison Between a Functional Method (FASAY) and Next Generation Sequencing (NGS)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3266-3266
Author(s):  
Cécile Bally ◽  
Aline Renneville ◽  
Lionel Adès ◽  
Claude Preudhomme ◽  
Hugues de Thé ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Lower Risk ◽  
Sanger Sequencing ◽  
Tp53 Mutation ◽  
P53 Protein ◽  
Next Generation ◽  
Tp53 Mutations ◽  
The Cost ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background TP53 mutations inactivating p53 protein, often associated with loss of the remaining TP53 allele through 17p deletion, are major prognostic factors in many hematological malignancies, including CLL, myeloma, AML and MDS. In AML and MDS, they are usually associated with complex karyotype (including del 17p) and very poor prognosis (Blood 1991, 78(7):1652-7 , Bejar, NEJM 2011), including after allogeneic SCT (Middeke JM, Blood 2014) but they are also seen in lower risk MDS with isolated del 5q, where they confer resistance to Lenalidomide (Jadersten, JCO 2011). The advent of Next Generation Sequencing (NGS) techniques has improved the detection of such mutations, by allowing the identification of small mutated clones. Other detection methods may prove interesting, especially functional methods like FASAY ( Functional Assay of Separated Allele in Yeast) , an easy and sensitive method that detects TP53 mutations by assessing the p53 function as transcription factor (Flaman et al, PNAS 1995). We compared the detection of TP53 mutations in MDS and AML by FASAY and NGS approaches. Methods The 84 patients analyzed included 10 AML, 10 higher risk MDS, and 64 lower risk MDS with del 5q. RNA and DNA were extracted from marrow mononuclear cells. TP53 mutations were detected on RNA by FASAY where, after amplification of the TP53 mRNA, the PCR product is co transfected with an open gap repair plasmid leading, by homologous recombination, to p53 protein expression in the yeast. The yeast strain used is dependent on p53 functionality for growth and color and detection of more than 10% of small red yeast colonies defines a non-functional FASAY result. All non-functional FASAY were confirmed by the split versions of the test and TP53 defects were characterized by Sanger sequencing. The detection limit is around 10% in our hands (Manie E, Cancer Res 2009). In parallel, TP53 mutations were detected on DNA by NGS using the IRON II plate design and pyrosequencing on a GS Junior System (Roche). (Kohlmann, Leukemia 2011).FASAY (+Sanger sequencing) and NGS were performed in two different labs. Results By FASAY, 47 patients (56%) had a functional p53 and 37 cases (44%) a non-functional p53 and a mutation was confirmed by Sanger in all non functional cases. By NGS analysis, no TP53 mutation was found in 47 cases (56%) and a mutation was detected in 37 cases (44%). In the 37 mutated cases by NGS, the median proportion of mutated allele was 35% (range 3 to 99%), including a median of 72%, 35%, 25 % in AML, higher risk MDS and lower risk MDS with del 5q, respectively. The mutated clone size was lower than 10% in only 2 patients who both had lower risk MDS with del 5q (3 and 6%, respectively). A perfect correlation between FASAY and NGS was found in 80 (95.5%) cases. The 4 discordant cases included a mutation detected only by FASAY in 2 cases, and only by NGS in 2 cases. Undetected mutations by NGS were insertions of intronic sequences (intron 9) not explored by the technique used. These insertions resulted in non-functional protein well detected by FASAY which analyses the global cDNA sequence including splicing defects. Undetected mutations by FASAY were mutations in which the percentage of mutated alleles was less than 10% (3% and 6 % respectively). Finally, while the cost of NGS analysis for TP53 mutation is around 200 euros when performed alone (and around 2000 euros when combined to analysis of the 30 main other genes involved in MDS and AML), the cost of the FASAY technique is around 20 euros (prices including reagents only). Conclusion The FASAY technique is a cheap method, that in spite of a sensitivity of only 10%, was able to detect 98% of TP53 mutations detected by NGS. In fact those mutations appear to involve generally relatively large clones in MDS and AML. FASAY could also detect 2 atypical intronic mutations overlooked by NGS. Demonstrating in such difficult cases that the resulting p53 protein is non functional and therefore probably has pathophysiological significance, is an advantage of FASAY .The combination of the 2 methods, and especially the combination of DNA and RNA analysis, may be useful in such cases. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparison of TP53 Alterations in Hematological Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4819-4819
Author(s):  
Anna Stengel ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
Susanne Schnittger ◽  
Melanie Zenger ◽  
...  
Keyword(s):  
Burkitt Lymphoma ◽  
Tp53 Mutation ◽  
Hematological Malignancies ◽  
Complex Karyotype ◽  
Mutation Load ◽  
Employment Equity ◽  
Copy Number State ◽  
Tp53 Mutations ◽  
Cytogenetic Aberrations ◽  
Equity Ownership

Abstract Background: TP53 is altered in ~50% of human cancers. Alterations include mutations and deletions. Both frequently occur together, supporting the classical "two-hit" hypothesis for tumor-suppressor genes. Aim: Comparison of TP53 mutation/deletion patterns in different hematological malignancies, including AML, MDS, ALL, Burkitt lymphoma, CLL and T-PLL. We analyzed (i) the frequencies of TP53 mutations and deletions, (ii) the types of mutation, (iii) the mutation load, (iv) the correlations to cytogenetic aberrations, (v) the age dependency, and (vi) impact on survival. Patient cohort and methods: A total of 3383 cases (AML: n=858, MDS: n=943, ALL: n=358, Burkitt lymphoma: n=25, CLL: n=1148 and T-PLL: n=51) were analyzed for TP53 deletions by interphase FISH determining the copy number state and for TP53 mutations by next-generation amplicon deep sequencing. Karyotype data was available for all cases. Results: Overall, alterations in TP53 were detected in 361/3383 cases (11%; 186 cases with mutation only (mut only), 51 cases with deletion only (del only), 124 cases with mutation and deletion (mut+del)). Regarding the respective entities, the highest frequency of TP53 alterations was observed in patients with Burkitt lymphoma (total alteration frequency: 56%, mut+del: 12%, mut only: 44%, no case del only). Alterations in TP53 also occured with a high incidence in patients with T-PLL (total: 30%; mut+del: 10%; mut only: 4%; del only: 16%) followed by cases with ALL (total: 19%; mut+del: 6%; mut only: 8%; del only: 5%) and AML (total: 13%; mut+del: 5%; mut only: 7%; del only: 1%). By contrast, TP53 alterations occurred less frequently in patients with CLL (total: 8%; mut+del: 4%; mut only: 3%; del only: 1%) and MDS (total: 7%; mut+del: 1%; mut only: 5%; del only: 1%). Missense mutations were found to be the most abundant mutation type in all entities analyzed with a frequency ranging from 71% - 88%. In all entities mainly one mutation per case was detected; however, MDS cases were found to harbour a statistically increased proportion of cases with two mutations compared to the other entities (p = 0.003). High TP53 mutation loads were detected in T-PLL (median: 88%) and AML (47%), whereas the lower ones were found in ALL (28%), Burkitt lymphoma (39%), MDS (39%), and CLL (36%). A strong correlation of TP53 alterations with a complex karyotype was observed in AML (of patients with TP53 alteration: 5% with normal karyotype, 67% with complex karyotype, 28% with other aberrations), ALL (16% normal, 45% complex, 39% other), MDS (14% normal, 53% complex, 33% other), and T-PLL (20% normal, 47% complex, 33% other). By contrast, in CLL and Burkitt lymphoma, TP53 alterations were mainly correlated with other aberrations (CLL: 10% normal, 30% complex, 60% other; Burkitt: 29% normal, 0% complex, 71% other). TP53 mut and TP53 mut+del were significantly more frequent in patients ≥ 60 vs < 60 years in AML (9% vs. 2% for mut only, p < 0.001; 7% vs. 2% for mut+del, p = 0.001) and ALL (12% vs. 6% for mut only, p < 0.001; 13% vs. 3% for mut+del, p = 0.001). By contrast, no such differences were observed for patients with CLL, MDS, T-PLL and Burkitt lymphoma. Moreover, TP53 alterations (especially of TP53 mut+del) had a significant negative impact on OS in all entities except for T-PLL and Burkitt lymphoma, most probably due to their overall short OS or due the lower number of cases. Conclusion: The frequency of TP53 mutations and/or deletions as well as the mutation load clearly varied between different hematological malignancies with the highest incidence of TP53 mut in patients with Burkitt lymphoma (56%) and a rather low frequency in CLL (7%) and MDS (6%). TP53 del were frequent in patients with T-PLL (26%) and Burkitt lymphoma (12%) and are hardly found in MDS cases (2%). TP53 alterations are correlated to higher age in AML and ALL. Moreover, alterations in TP53 are correlated to a short OS and to a complex karyotype, with the exception of Burkitt lymphoma and CLL, were they were found to be associated to other cytogenetic aberrations. Thus, TP53 mutations and deletions need further investigation in the future, especially regarding their clinical impact in different hematologic entities. Disclosures Stengel: MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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