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 >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.

SNP Array-Based Analysis of Chromosome 17 Reveals Biallelic TP53 Mutations Due to Uniparental Disomy 17p in Advanced MDS and AML with Cooperating Deletions of Chromosomes 5 and 7

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2521-2521 ◽  
Author(s):  
Monika Jasek ◽  
Lukasz P. Gondek ◽  
Nelli Bejanyan ◽  
Ramon V. Tiu ◽  
Jungwon Huh ◽  
...  
Keyword(s):  
Median Survival ◽  
Tp53 Mutation ◽  
Clinical Phenotype ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Chromosome 17 ◽  
Missense Mutations ◽  
Complex Karyotype ◽  
Tp53 Mutations ◽  
Myeloid Malignancies

Abstract Areas of loss of heterozygosity (LOH) can be precisely delineated using single nucleotide polymorphism arrays (SNP-A) allowing for detection of submicroscopic chromosomal defects and segmental somatic uniparental disomy (UPD) not revealed by metaphase cytogenetic analysis (MC). This study focused on aberration of chromosome 17. We analyzed marrow specimens in 1162 MDS/AML by MC and found 39 patients whose karyotype involved monosomy 17. All had a complex karyotype, aggressive histomorphologic features (1/39 low risk, 26/39 advanced MDS/sAML, 2/39 MDS/MPD, and 10/39 pAML) with a median survival of 3 months. In addition to loss of chromosome 17, 35/39 patients also showed either −5/del(5q) (N=10), −7/del(7q) (N=2), or both (N=23). To better delineate the boundaries of LOH on 17th chromosome, we analyzed a subset of 532 patients by SNP-A and identified 43/532 samples with an abnormal chromosome 17; 28 had interstitial deletions and 15 had somatic UPD. In 17/19 samples with monosomy 17 by MC, SNP-A revealed a deletion in 17p or 17q, indicating incomplete loss of chromosome 17 material. SNP-A yielded a total of 11 additional lesions on 17q not detected by MC. We were able to define two commonly deleted regions (CDR1 and CDR2). CDR1 (bp 6,828,482 to 8,075,871; 1.25 Mb) encompassed around 90 genes, including TP53, and was present in 11/14 samples with del17p. CDR2 (bp 25,320,435 to 27,355,332; 2Mb) was detected in 7/14 patients and encompassed approximately 33 genes, including NF1. Overall, the frequency of UPD17 was high: 17p UPD was detected in 7 and 17q in 8 samples analyzed. In all cases with 17p UPD, the region of UPD overlapped with CDR1. CDR2 overlapped with the region of 17q UPD in 4/8 samples. In analogy to monosomy 17, 18/21patients with LOH 17p (7 UPD, 14 losses) had a complex karyotype, 21/21 had aggressive histomorphologic features (1/21 RCMD, 3/21 RCMD-RS, 6/21 RAEB-1/2, 3/21 pAML, 8/21sAML) and a poor prognosis with a median survival of 2.6 months. Moreover, in 13/14 patients with del(17p) by SNP-A, −5/del(5q) (N=1) or both −5/del(5q) and −7/del(7q) (N=12) were present. One patient did not show deletions of chromosomes 5 or 7, but had del (4)(q26) and del(6)(q23.2). No patient had del(17p) as the sole abnormality. Strong association between 17p UPD and abnormalities of chromosomes 5 and/or 7 was also noted: of 7 patients with 17p UPD, 3 had 5/del(5q), 1 showed −7/del(7q), and 3 had −5/del(5q) and −7/del(7q). We hypothesized that LOH within the 17p CDR1 that includes TP53 might be associated with a distinct clinical phenotype and point toward pathogenic TP53 mutations. Overall, 18 instances of 17p LOH included the TP53 locus. When TP53 exons 5–9 were screened for mutations in patients with 17p LOH, we found biallelic TP53 mutations in 5/6 patients with somatic 17p UPD and in 6/8 patients with 17p deletions. We detected 10 missense mutations and 1 insertion. All missense mutations were located in the DNA-binding domain of TP53 (4/10 in exon 5: C141Y, V172F, C176Y, H179Q; 2/10 exon 6: H193N, H193R; 1/10 exon 7: R249G and 3/10 exon 8: V272L, V272M, R273H). Our study demonstrates that LOH of 17p in myeloid malignancies should prompt consideration of TP53 mutation. TP53 mutation is linked with an aggressive clinical phenotype and is highly associated with partial or complete loss of chromosomes 5 and/or 7. To our knowledge this is the first report of biallelic TP53 mutations due to UPD17p in myeloid malignancies, and indicates that both heterozygous and homozygous mutations can be encountered and comprise part of the pathologic continuum of the selection process of malignant myeloid clones.

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.

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.

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.

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.

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.

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.

scholarly journals TP53 Abnormality in Myelodysplastic Syndrome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5410-5410
Author(s):  
Fei Huang ◽  
Yu Chen ◽  
Yuxing Zhu ◽  
Chun Qiao ◽  
Sixuan Qian ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Disease Progression ◽  
Tp53 Mutation ◽  
Conflicts Of Interest ◽  
Multiple Time ◽  
Complex Karyotype ◽  
Newly Diagnosed ◽  
Tp53 Mutations ◽  
Molecular Abnormalities ◽  
Highly Correlated

TP53 (tumor suppressor gene P53), one of the most important tumor suppressor genes, plays an important role in cell cycle arrest, cell senescence, apoptosis, differentiation and metabolism. The TP53 gene is located on 17p13.1, its encoded product is the transcription factor P53 protein, which is known as the "the guardian of the genome". Alterations of TP53 include mutations and deletions and are generally associated with advanced stages of disease, insufficient therapy-response and poor prognosis. The main purpose of our study was to comprehensively analyze the TP53 mutation and 17p deletion in MDS in our single center. To better understand the relationship between TP53 abnormality and clinical phenotype, prognosis, leukemia transformation, therapeutic response of MDS. Next generation sequencing (NGS) method combining with cytogenetics analysis were used, 36 common related AML/MDS/MPN related genes such as TP53, TET2, WT1, ASXL1, U2AF1, RUNX1, etc were covered. According to the 2016 WHO classification and prognosis score system and from June 2011 to June 2017, 88 newly diagnosed MDS patients including 17 MDS-SLD, 32 MDS-MLD,6 MDS-RS,19 MDS-EB-1,11 MDS-EB-2 and 2 MDS-U, 1 5q- syndrome were enrolled. TP53 mutation/deletions were found in twenty-two (25%) of the 88 newly diagnosed MDS patients, among them,7 MDS-SLD, 4 MDS-MLD, 2 MDS-RS, 1 5q-, 6 MDS-EB-1 and 6 MDS-EB-2. TP53 mutation/deletions cases had a higher proportion of bone marrow blasts compared with TP53 negative cases (P=0.009), At the same time, TP53 positive were highly correlated with MDS-EB-2 subtype (P=0.025), complex karyotype (P<0.001). Based on a median follow-up time of 21(1-267) months in all pts, 13 patients (14.8%) progressed to AML and pts with TP53 mutation/deletions tended to progress to AML (P=0.056) with a shorter OS (P=0.005) and PFS (P=0.001). NGS data of accompanying mutation in other classical leukemia genes shown that compound TP53 and U2AF1 mutations were significantly associated with disease progression. For TP53 mutation/deletion group (n=22), we further sequenced the TP53 status at multiple time point of pre and after DAC treatment, results shown that all patients had persistent TP53 positive status before and after treatment. In conclusion, our results indicate that in MDS TP53 mutation/deletions is highly correlated with MDS-EB-2 subtype, IPSS high-risk group, and complex karyotype. TP53 mutations that occur in the early stages of MDS may contribute to disease progression and leukemia transformation in conjunction with other molecular abnormalities. DAC improves outcomes in patients with TP53 mutation/deletion but may not clear TP53 mutations. Disclosures No relevant conflicts of interest to declare.

CBIO-18. TP53-MUTANT OLIGODENDROGLIOMA: A SINGLE INSTITUTION CASE SERIES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi30-vi31
Author(s):  
Mason Webb ◽  
Sani Kizilbash ◽  
Thomas Kollmeyer ◽  
Robert Jenkins ◽  
Sarah Sung ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Tp53 Mutation ◽  
Case Series ◽  
Molecular Testing ◽  
Diffuse Glioma ◽  
Who Grade ◽  
Tp53 Mutations ◽  
Grade Ii ◽  
Who Grade Iii ◽  
Grade Iii

Abstract TP53 mutations are frequent in IDH-mutant astrocytomas but unusual in oligodendroglioma and the clinical significance of TP53 mutations in oligodendroglioma are not well characterized. We reviewed genetically defined oligodendroglioma (i.e., IDH-mutant, whole-arm 1p/19q-codeleted diffuse glioma) cases that were molecularly profiled (2017-2020) at our institution and identified 7 cases with TP53 mutation (9%; n=76). Molecular testing was performed using targeted neuro-oncology NGS panel (50-gene mutation and/or 187-gene mutation/rearrangement) and OncoScan™ microarray. Four (of 7) patients were female. Median age at diagnosis was 43 years (range, 23-63). Most common presenting symptom was seizures (3 of 7). All tumors were supratentorial. Histologically, 3 tumors were WHO grade II and 4 were WHO grade III. Two (of 3) patients with a WHO grade II tumor underwent biopsy and radiotherapy at diagnosis followed by temozolomide at recurrence (progression at 67 and 157 months after diagnosis; overall survival of 124 and 201 months). Three (of 4) patients with a WHO grade III tumor were diagnosed within the last two years and are currently progression-free after standard therapy. Molecularly, in addition to TP53 mutation(s), all cases had an IDH1 and TERT promoter mutation as well as other gene mutation(s) including FUBP1 (n=5), SETD2 (n=4), PIK3R1 (n=4), PIK3CA (n=3), NF1 (n=3) and CIC (n=3). In 3 (of 7) cases, the mutational profile with high mutation count enriched for C &gt;T/G &gt;A transitions was highly suggestive of a hypermutation phenotype (2 cases were recurrent tumors treated with temozolomide; a recurrent and a treatment-naïve tumor had mismatch repair gene mutation). Five (of 7) cases, including the 3 hypermutant cases, lacked functional TP53 (1 case with 2 mutations, 2 cases with 1 mutation plus loss of other copy, 2 cases with 1 mutation plus copy neutral loss-of-heterozygosity). TP53 mutations are uncommon in oligodendroglioma and appear enriched in hypermutant tumors.

The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3892-3892
Author(s):  
Claudia Haferlach ◽  
Melanie Zenger ◽  
Vera Grossmann ◽  
Frank Dicker ◽  
Sabine Jeromin ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Class Ii ◽  
Class I ◽  
Complex Karyotype ◽  
Mutation Status ◽  
Tp53 Mutations ◽  
Total Cohort ◽  
Additional Chromosome ◽  
Equity Ownership ◽  
The Impact

Abstract Abstract 3892 Background: 13q deletions (del(13q)) are the most frequent abnormalities in CLL and, if present as a sole abnormality, associated with favorable outcome. Since the size of the deletion varies considerably, class I (del(13q) not including the RB1 locus) and class II (del(13q) including the RB1 locus) deletions were defined. Previous data suggested that class II deletions were associated with genomic complexity and an unfavorable clinical course. However, confirmation in a large patient cohort was lacking. Aim: Cytogenetic and molecular genetic characterization of patients with class I and class II deletions and evaluation of the impact on outcome. Patients and Methods: 263 cases with newly diagnosed CLL and del(13q) were analyzed by FISH using probes for RB1, D13S25, D13S319 (13q14), ATM (11q22), TP53 (17p13), SEC63 (6q21) and 12 cen. Data from chromosome banding analyses (CBA) (n=263), IGHV mutation status (n=230) and TP53 mutation status (n=206) were also available. Results: 145/263 patients (55.1%) showed a class I and 118 cases (44.9%) a class II deletion. In 79/263 patients (30%) a homozygous del(13q) was observed. No significant difference in frequency of homozygous deletions was observed between cases with class I vs class II deletions (48/145 (33.1%) vs 31/118 (26.3%)). Abnormalities in addition to del(13q): Based on FISH data 66 cases (25.1%) showed abnormalities in addition to del(13q) (del(6q): 5, del(11q): 28, +12: 27, del(17p): 11). The frequency of additional abnormalities did not differ between patients with class I vs class II deletions (25.5% vs 24.6%). Considering also CBA 101 patients (38.4%) showed additional abnormalities. A complex karyotype defined as 3 or more abnormalities in addition to del(13q) was observed in 34 cases (12.9%) and was more frequent in cases with class II deletion (17.8% vs 9.0%, p=0.042). The mean number of abnormalities per case was significantly higher in patients with class II deletions (1.25 vs 0.7, p=0.002). Patients with homozygous del(13q) less frequently showed additional chromosome abnormalities compared to patients with heterozygous del(13q) (22.8% vs 45.1%, p=0.001). IGHV mutation status: In the total cohort, 156/230 patients (67.8%) showed a mutated and 74 (32.2%) an unmutated IGHV status. No difference with respect to the IGHV mutation status was observed between class I vs class II cases. However, an unmutated IGHV status was more frequent in cases with additional abnormalities detected by FISH or CBA compared to those without (52.6% vs 25.4%, p<0.0001 and 48.3% vs 22.4%, p<0.0001). A mutated IGHV status was more frequent in patients with homozygous as compared to heterozygous del(13q) (81.2% vs 62.1%, p=0.005). TP53 mutation status: TP53 mutations were observed in 15/206 cases (7.3%). The TP53 mutation frequency did not differ between class I vs class II patients (6.9% vs 7.8%). However, TP53 mutations were more frequent in cases with additional abnormalities detected by FISH or CBA as compared to those without (18.8% vs 3.8%, p=0.002 and 13.2% vs 3.8%, p=0.023), in cases with complex karyotype (19.2% vs 5.6%, p=0.027), and in cases with TP53 deletions detected by FISH as compared to those without (70.0% vs 4.1%, p<0.0001). Overall survival and time to treatment: OS at 3 yrs in the total cohort was 94% (median time of follow-up of 3.0 yrs). Only Binet stage B/C was significantly associated with shorter OS (p=0.014; relative risk (RR): 6.56). A trend for shorter OS was observed for additional TP53 mutations and/or deletions, while no difference in OS was observed between class I vs class II and homozygous vs heterozygous deletions. The following parameters were associated with longer TTT: no additional abnormalities present in CBA or FISH (p=0.009; RR: 0.55; p=0.010; RR: 0.54), and a mutated IGHV status (p<0.0001; RR: 0.381). A complex karyotype (p=0.040; RR: 1.80) and ATM deletions (p=0.013; RR: 2.04) were associated with shorter TTT. Conclusions: 1. Neither the size nor homozygosity of del(13q) showed impact on OS or TTT. However, a mutated IGHV status and the absence of additional abnormalities were associated with longer TTT. Patients with an additional del(11q) or a complex karyotype showed shorter TTT. 2. A complex karyotype was significantly associated with class II deletions. 3. CLL with del(13q) can be further subdivided by the RB1 deletion status, additional chromosome abnormalities based on CBA and IGHV mutation status. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

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