DDRE-14. OPTIMIZING MDM2 INHIBITION FOR THE TREATMENT OF HIGH-GRADE GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi77-vi77
Author(s):  
Veronica Rendo ◽  
Leslie Lupien ◽  
Nicholas Khuu ◽  
Kristine Pelton ◽  
Lara Elcavage ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
Tp53 Gene ◽  
Resistance Mechanisms ◽  
High Grade ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Activating Mutations ◽  
Cycle Arrest ◽  
Transcriptional Changes ◽  
Mdm2 Inhibitor

Abstract A majority of high grade gliomas retain a wild-type TP53 gene and are amenable to strategies for activation of the pathway to inhibit tumor growth. The interaction between p53 and MDM2 has served as target for such strategies currently in clinical trials for glioblastoma. As the effects and resistance mechanisms of MDM2 inhibition (MDM2i) remain poorly understood in glioma, we performed genomic and transcriptomic analyses in patient-derived models to better characterize sensitive tumors and identify putative biomarkers of drug response. Treatment with an MDM2 inhibitor (KRT232/AMG232) impaired the growth of cell lines with wild-type TP53 status, particularly in tumors with amplification of MDM2/4 or PPM1D activating mutations. Treatment with KRT232 upregulated both cell cycle arrest and apoptotic cellular responses, with unique temporal and transcriptional differences correlated with MDM2/4 or PPM1D status. In other tumors resistance to MDM2i is mainly mediated by TP53 mutations, but in a subset of chronic KRT232-treated glioma models we noted lack of TP53 mutations and identified cell state and transcriptional changes as potentially more treatable mediators of resistance.

scholarly journals OMRT-6. Optimizing MDM2 inhibition for the treatment of high-grade glioma

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Veronica Rendo ◽  
Leslie Lupien ◽  
Nicholas Khuu ◽  
Kristine Pelton ◽  
Sophie Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Response ◽  
High Grade Glioma ◽  
High Grade ◽  
Wild Type ◽  
P53 Pathway ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Transcriptional Changes ◽  
Wild Type P53

Abstract Over 80% of high-grade gliomas have alterations in members of the p53 pathway, a central regulator of cell cycle progression and apoptosis that becomes activated in response to cellular stress and DNA damage. For tumors that retain wild-type p53, pathway deregulation frequently occurs through the amplification of negative regulators of p53, including the E3 ubiquitin ligase MDM2. The p53/MDM2 interaction axis has served as basis for the development of several classes of MDM2 inhibitors, with AMG232 being the most potent molecule currently undergoing clinical evaluation. As the effects of MDM2 inhibition (MDM2i) remain poorly understood in high-grade glioma, we performed genomic and transcriptomic analyses in patient-derived models to better characterize sensitive tumors and identify putative biomarkers of drug response. Treatment with AMG232 impaired the growth of cell lines with wild-type p53 status, particularly in tumors with additional amplification of MDM4 or PPM1D activating mutations. Treatment with AMG232 upregulated both cell cycle arrest and apoptotic cellular responses, as measured by annexin V/PI staining and immunoblotting. Interestingly, the dynamics of these two downstream p53 signaling axis were dependent on treatment duration across models. In addition to p53 pathway activation and apoptotic induction, RNA-sequencing revealed MDM2i to be associated with the activation of oncogenic MAPK and KRAS signaling as well as epithelial to mesenchymal transition markers. In most solid tumors, resistance to MDM2i is mainly mediated by acquisition of p53 inactivating mutations. We hypothesized that resistance mechanisms in glioma may be partially driven by transcriptional changes, as these tumors consist of subpopulations with diverse cell differentiation states. By chronic AMG232 treatment, we have developed in vitro and in vivo models of acquired MDM2i resistance that are not mediated by p53 inactivation. Ongoing work is focused on characterizing the transcriptional profile of these cells to identify transcriptional changes leading to decreased drug response.

CBIO-11. HISTONE H3.3 G34R/V MUTATIONS STIMULATE PEDIATRIC HIGH-GRADE GLIOMA FORMATION THROUGH THE INDUCTION OF CHROMOSOMAL INSTABILITY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi29-vi29
Author(s):  
Charles Day ◽  
Florina Grigore ◽  
Alyssa Langfald ◽  
Edward Hinchcliffe ◽  
James Robinson
Keyword(s):  
Gene Regulation ◽  
Chromosomal Instability ◽  
High Grade Glioma ◽  
Kinase Assay ◽  
High Grade ◽  
Newborn Mice ◽  
Cycle Arrest ◽  
Epigenetic Gene Regulation ◽  
Diploid Cells

Abstract H3.3 G34R/V mutations are drivers of high-grade pediatric glioma (pHGG). H3.3 G34R/V mutations are linked to altered H3.3 K36 trimethylation (H3K36me3); implicating epigenetic gene regulation as a possible contributor to pHGG formation. Here we show that H3.3 G34R/V also induces chromosomal instability (CIN); a hallmark of pHGG. If CIN promotes pHGG formation is unknown. We observed that H3.3 G34 mutant pHGG cells have reduced mitotic H3.3 S31 phosphorylation compare to WT H3.3 cell lines. And, H3.3 G34R reduced Chk1 phosphorylation at S31 by >90% in an in vitro kinase assay. Chk1 regulates chromosome segregation through phosphorylation of pericentromeric H3.3 S31 during early mitosis. Overexpression of H3.3 G34R or non-phosphorylatable S31A in H3.3 WT, diploid cells caused a significant increase in CIN. Likewise, H3.3 G34 mutant pHGG cells have significantly elevated rates of CIN as compare to H3.3 WT pHGG cells. During normal cell division, phospho-S31 is lost in anaphase. However, following chromosome missegregation, phospho-S31 spreads and stimulates p53-induced cell cycle arrest. Here we show that WT p53 cells expressing mutant G34 fail to arrest following chromosome mis-segregation. These studies demonstrate that H3.3 G34R/V mutations are sufficient to transform normal, diploid cells into proliferating CIN cells. To determine if this process contributes to tumorigenesis, we used RCAS Nestin-TVA mice to overexpress H3.3 WT, G34R, or S31A – P2A-linked to PDGFB expression in glial precursor cells of newborn mice. Over 100 days, S31A and G34R mice had drastically reduced survival (averaging 77, 81, and 100 days for S31A, G34R, and WT). Furthermore, most G34R and S31A mice developed HGG, while H3.3 WT mice remained tumor-free. Our work implicates CIN as a driver of H3.3 G34 mutant pHGG formation. Our ongoing studies utilize K36M and double mutants to further define the contributions of S31 phosphorylation (CIN) and H3K36me3 (epigenetic gene regulation) to tumorigenesis.

scholarly journals Radiological assessment schedule for high-grade glioma patients during the surveillance period using parametric modeling

2020 ◽  
Author(s):  
So Young Ji ◽  
Jongjin Lee ◽  
Joo Ho Lee ◽  
Soon-Tae Lee ◽  
Jae Kyung Won ◽  
...  
Keyword(s):  
Standard Treatment ◽  
Risk Group ◽  
High Grade Glioma ◽  
Parametric Model ◽  
Parametric Modeling ◽  
Progression Rate ◽  
High Grade ◽  
Radiological Assessment ◽  
Wild Type

Abstract Background An optimal radiological surveillance plan is crucial for high-grade glioma (HGG) patients, which is determined arbitrarily in daily clinical practice. We propose the radiological assessment schedule using a parametric model of standardized progression-free survival (PFS) curves. Methods A total of 277 HGG patients (178 glioblastoma (GBM) and 99 anaplastic astrocytoma (AA)) from a single institute who completed the standard treatment protocol were enrolled in this cohort study and retrospectively analyzed. The patients were stratified into each layered risk group by genetic signatures and residual mass or through recursive partitioning analysis. PFS curves were estimated using the piecewise exponential survival model. The criterion of a 10% progression rate among the remaining patients at each observation period was used to determine the optimal radiological assessment time point. Results The optimal follow-up intervals for MRI evaluations of the isocitrate dehydrogenase (IDH) wild-type GBM was every 7.4 weeks until 120 weeks after the end of standard treatment, followed by a 22-week inflection period and every 27.6 weeks thereafter. For the IDH mutated GBM, scans every 13.2 weeks until 151 weeks are recommended. The optimal follow-up intervals were every 22.8 weeks for the IDH wild-type AA, and 41.2 weeks for the IDH mutated AA until 241 weeks. Tailored radiological assessment schedules were suggested for each layered risk groups of the GBM and the AA patients. Conclusions The optimal schedule of radiological assessments for each layered risk group of patients with HGG could be determined from the parametric model of PFS.

scholarly journals H3K27M and TERT Promoter Mutations Are Poor Prognostic Factors in Surgical Cases of Adult Thalamic High-Grade Glioma

2021 ◽  
Author(s):  
Yoshinari Osada ◽  
Ryuta Saito ◽  
Ichiyo Shibahara ◽  
Keisuke Sasaki ◽  
Takuhiro Shoji ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Molecular Characteristics ◽  
High Grade ◽  
Wild Type ◽  
Target Sequencing ◽  
Dismal Prognosis ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Abstract Background Thalamic high-grade gliomas (HGGs) are rare tumors with a dismal prognosis. H3K27M and telomerase reverse transcriptase promoter (TERTp) mutations reportedly contribute to poor prognoses in HGG cases. We investigated the outcomes of surgically treated adult thalamic HGGs to evaluate the prognostic significance of H3K27M and TERTp mutations. Methods We retrospectively analyzed 25 adult patients with thalamic HGG who underwent maximum surgical resection from January 1997 to March 2020. The histological and molecular characteristics, progression-free survival (PFS), and overall survival (OS) of the patients were compared. For molecular characteristics, target sequencing was used to determine the H3F3A, HIST1H3B, and TERTp mutations. Results H3K27M mutations were detected in 12/25 (48.0%) patients. TERTp mutations were not detected in H3K27M-mutant gliomas but were detected in 8/13 (61.5%) of H3 wild-type gliomas. Although it was not significant, H3K27M-mutant gliomas tended to have a shorter PFS (6.7 vs. 13.1 months; P = 0.2928) and OS (22.8 vs. 24.4 months; P = 0.2875) than H3 wild-type gliomas. Moreover, the prognosis of TERTp-mutant gliomas was as poor as that of H3K27M-mutant gliomas. Contrary, five gliomas harboring both H3 and TERTp wild-type showed a better median PFS (59.2 vs. 6.4 months; P = 0.0456) and OS (71.8 vs. 24.4 months; P = 0.1168) than those harboring H3K27M or TERTp mutations. Conclusions TERTp-mutant gliomas included in the H3 wild-type glioma group limited patient survival as they exhibited an aggressive course similar to H3K27M-mutant gliomas. Comprehensive molecular work-up for the H3 wild-type cases may further confirm this finding.

Next Generation Sequencing (NGS) of TP53 Gene Allows to Identify a Very High Risk Group of Philadelphia Negative Acute Lymphoblastic Leukemia (ALL) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3796-3796
Author(s):  
Silvia Salmoiraghi ◽  
Greta Ubiali ◽  
Manuela Tosi ◽  
Barbara Peruta ◽  
Marie Lorena Guinea Montalvo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Tp53 Mutation ◽  
Lymphoblastic Leukemia ◽  
Tp53 Gene ◽  
Wild Type ◽  
Poor Clinical Outcome ◽  
Tp53 Mutations ◽  
Next Generation Sequencing Ngs ◽  
Roche Diagnostics ◽  
Generation Sequencing

Abstract Background and Aim of the Study For both childhood and adult Acute Lymphoblastic Leukemia (ALL) patients, clinical risk factors such as age, white cell count, response to steroids, time to complete remission, as well as biologic characteristics such as immunophenotype and cytogenetic at diagnosis are important but not sufficient in predicting clinical outcome. Aberrations of TP53 play a crucial role in the molecular pathogenesis of leukemias and lymphomas in which their presence is associated to disease progression and represents a strong predictor of poor clinical outcome. In childhood ALL, hereditary and acquired TP53 mutations are involved both in the pathogenesis and progression of the disease. In adult ALL, TP53 mutations are frequent in patients negative for recurrent fusion genes and correlate with poor response to induction therapy (Chiaretti S. et al, Haematologica 2013). The aim of this study was to evaluate the impact of TP53 alterations, analyzed by Next Generation Sequencing (NGS), on the outcome of a cohort of T (n= 57) and B (n= 114) precursor, Philadelphia (Ph) negative, adult ALL patients enrolled into the NILG-ALL 09/2000 clinical trial (ClinicalTrials.gov identifier: NCT00358072, Bassan R. et al, Blood 2009) in which molecular minimal residual disease was used to guide post-remissional therapy. Patients and Study design Among the 171 patients who were investigated for TP53 mutations, 16 proved also positive for t(4;11) and 3 for t(1;19). We analyzed DNA isolated from mononuclear cells obtained from bone marrow or peripheral blood samples containing at least 30% of blasts at diagnosis. The TP53 gene was sequenced using 454 ultra-deep sequencing (Roche Diagnostics) for alterations in exons 4 to 11, following the protocol developed in the IRON-II consortium. The sequencing data were analyzed by the Roche Diagnostics GS Run Browser and GS Amplicon Variant Analyzer software. The probabilities of survival were estimated using the Kaplan Meier method. The log-rank test was used to compare survival probabilities between subgroups of patients. Results and Discussion The data obtained by NGS allowed to identify 15 coding mutations detected in the DNA binding domain region (exons 5 to 8). These alterations were observed at diagnosis in 14 patients (8%), (11 B-precursor ALL and 3 T-ALL). In 12 cases these aberrations were single nucleotide changes, in 2 cases we found a duplication (one of 4 and the other of 8 nucleotides) and in one case there was an 11 base pair DNA insertion. Remarkably, all of these DNA alterations led to missense or frame-shift mutations that introduced a premature stop codon. Moreover, they were detected with a wide range of allele burden (from 5% to 97%) pointing out that TP53 mutations can be present at diagnosis in different proportions within the leukemic clones. All patients carrying a TP53 alteration reached complete remission after induction therapy but 13 out of 14 suffered an early relapse. Frequency of relapses was significantly higher in mutated than in wild-type cases (p=0.019). Relapse DNA samples were available in 3 patients and in all of them we detected the same TP53 mutation found at diagnosis, indicating the presence of a stable mutated clone. The univariate analysis enlightens a clear relationship between TP53 mutation with an increasing age (p= 0.0003) but no correlation with other clinical features such as gender, hemoglobin, white blood count, platelets, percentage of blasts and cytogenetics at diagnosis. Moreover, patients with mutated TP53 showed a Disease Free Survival (DFS) and Overall Survival (OS) dramatically shorter than wild-type patients. The 2 years DFS was 43% in the TP53 non-mutated subjects compared to 7% in the mutated (p=0.0007). Similarly, the 2 years OS was of 50% in wild-type patients and of 7% in mutated patients (p=0.0011) (Figure 1). Conclusions In adult ALL, response to induction chemotherapy is not different in patients with a wild-type or a TP53 mutated gene, but in these latter cases the leukemia relapse rate is dramatically higher. The frequency of these mutations observed at diagnosis and the poor clinical outcome indicate the need of their identification during the diagnostic work up of adult ALL to guide treatment strategies. The use of a highly sensitive deep sequencing approach is crucial to identify also minor leukemic clones carrying TP53 mutations that may lead to the rapid emergence of a treatment resistant disease. Disclosures Kohlmann: AstraZeneca: Employment.

scholarly journals Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 124 ◽  
Author(s):  
Petros Christopoulos ◽  
Steffen Dietz ◽  
Martina Kirchner ◽  
Anna-Lena Volckmar ◽  
Volker Endris ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Lung Cancer Patients ◽  
Anaplastic Lymphoma ◽  
Nsclc Patients

Anaplastic lymphoma kinase (ALK) sequencing can identify resistance mechanisms and guide next-line therapy in ALK+ non-small-cell lung cancer (NSCLC), but the clinical significance of other rebiopsy findings remains unclear. We analysed all stage-IV ALK+ NSCLC patients with longitudinally assessable TP53 status treated in our institutions (n = 62). Patients with TP53 mutations at baseline (TP53mutbas, n = 23) had worse overall survival (OS) than patients with initially wild-type tumours (TP53wtbas, n = 39, 44 vs. 62 months in median, p = 0.018). Within the generally favourable TP53wtbas group, detection of TP53 mutations at progression defined a “converted” subgroup (TP53mutconv, n = 9) with inferior OS, similar to that of TP53mutbas and shorter than that of patients remaining TP53 wild-type (TP53wtprogr, 45 vs. 94 months, p = 0.043). Progression-free survival (PFS) under treatment with tyrosine kinase inhibitors (TKI) for TP53mutconv was comparable to that of TP53mutbas and also shorter than that of TP53wtprogr cases (5 and 8 vs. 13 months, p = 0.0039). Fewer TP53wtprogr than TP53mutbas or TP53mutconv cases presented with metastatic disease at diagnosis (67% vs. 91% or 100%, p < 0.05). Thus, acquisition of TP53 mutations at progression is associated with more aggressive disease, shorter TKI responses and inferior OS in ALK+ NSCLC, comparable to primary TP53 mutated cases.

scholarly journals The Value of Enhanced MR Radiomics in Estimating the IDH1 Genotype in High-Grade Gliomas

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Lei Niu ◽  
Wei-hua Feng ◽  
Chong-feng Duan ◽  
Ying-chao Liu ◽  
Ji-hua Liu ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
Validation Dataset ◽  
High Grade ◽  
Wild Type ◽  
Mr Images ◽  
Who Grade ◽  
Model Based ◽  
Idh Mutations ◽  
Who Grade Iii ◽  
Grade Iii

Background. The prognosis of IDH1-mutant glioma is significantly better than that of wild-type glioma, and the preoperative identification of IDH mutations in glioma is essential for the formulation of surgical procedures and prognostic assessment. Purpose. To explore the value of a radiomic model based on preoperative-enhanced MR images in the assessment of the IDH1 genotype in high-grade glioma. Materials and Methods. A retrospective analysis was performed on 182 patients with high-grade glioma confirmed by surgical pathology between December 2012 and January 2019 in our hospital with complete preoperative brain-enhanced MR images, including 79 patients with an IDH1 mutation (45 patients with WHO grade III and 34 patients with WHO grade IV) and 103 patients with wild-type IDH1 (33 patients with WHO grade III and 70 patients with WHO grade IV). Patients were divided into a primary dataset and a validation dataset at a ratio of 7 : 3 using a stratified random sampling; radiomic features were extracted using A.K. (Analysis Kit, GE Healthcare) software and were initially reduced using the Kruskal-Wallis and Spearman analyses. Lasso was finally conducted to obtain the optimized subset of the feature to build the radiomic model, and the model was then tested with cross-validation. ROC (receiver operating characteristic curve) analysis was performed to evaluate the performance of the model. Results. The radiomic model showed good discrimination in both the primary dataset ( AUC = 0.87 , 95% CI: 0.754 to 0.855, ACC = 0.798 , sensitivity = 85.5 % , specificity = 75.4 % , positive   predictive   value = 0.734 , and negative   predictive   value = 0.867 ) and the validation dataset ( AUC = 0.86 , 95% CI: 0.690 to 0.913, ACC = 0.789 , sensitivity = 91.3 % , specificity = 69.0 % , positive   predictive   value = 0.700 , and negative   predictive   value = 0.909 ). Conclusion. The radiomic model, based on the preoperative-enhanced MR, can effectively predict the IDH1 genotype in high-grade glioma.

scholarly journals COVD-18. POTENTIAL TO HARNESS SARS-COV-2 NEUROTROPISM IN THE DELIVERY OF ONCOLYTIC VIROTHERAPY FOR THE TREATMENT OF HIGH-GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii24-ii25
Author(s):  
Amanda Immidisetti ◽  
Sean Munier ◽  
Nitesh Patel
Keyword(s):  
Clinical Trials ◽  
High Grade Glioma ◽  
Oncolytic Viruses ◽  
Wild Type Virus ◽  
High Grade ◽  
Wild Type ◽  
Olfactory Pathway ◽  
Non Invasive ◽  
Pathogenic Virus ◽  
Tumor Cell Lysis

Abstract BACKGROUND High-grade gliomas (HGG) pose therapeutic challenges stemming from blood brain barrier, infiltrative growth, suppressed immune function, and tumor heterogeneity. Oncolytic viruses (OVs) are gaining traction for addressing these challenges. There is evidence that the SARS-CoV-2 glycoprotein spike binds the ACE-2 receptor in nasal epithelium and reaches the brainstem and thalamus via axonal transport through the olfactory pathway, making it an attractive candidate for OV therapy. Prior studies on chimerization of pathogenic virus-derived glycoprotein spikes with non-pathogenic strains exploit neurotropism of a wild-type virus while improving the safety profile of the resulting OV. We review, 1) the engineering of chimeric OVs used in the treatment of HGG; 2) potential for a novel chimeric virotherapy in which the SARS-CoV-2 glycoprotein spike can be used to deliver OV therapy intranasally; and 3) areas which warrant further investigation to develop this approach for clinical use. METHODS We performed an extensive review of chimeric OVs and specific modifications engineered to optimize safety and efficacy. Additionally, we assessed potential to use these principals to engineer the SARS-CoV-2 glycoprotein spike onto a non-pathogenic, replication competent virus to yield a novel chimeric for noninvasive, intranasal delivery. RESULTS Viruses with pathogenic properties in wild-type have been successfully used as components of OVs and have demonstrated potential in both preclinical and clinical trials. Outcomes show that despite wild-type virulence, notable toxicities were not observed in clinical trials, highlighting the potential of viral pseudotyping as a safe therapeutic approach. CONCLUSIONS The proposed method to utilize the SARS-CoV-2 glycoprotein in a novel chimeric poses advantages including 1) potential for non-invasive delivery, 2) therapy without need for maximal or uniform tumor coverage due to replication competence, 3) ability to reach infiltrative glioma cells, 4) potential to reach the brainstem, and 5) stimulation of host immunity through tumor cell lysis and antigen presentation

scholarly journals Mutations in TP53 Gene Is Independent Prognostic Factor for High Grade B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5402-5402
Author(s):  
Anna Evgenevna Misyurina ◽  
Vsevolod Andreevich Misyurin ◽  
Andrey Vitalievich Misyurin ◽  
Alla Mikhailovna Kovrigina ◽  
Sergey Kirillovich Kravchenko ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Prognostic Factor ◽  
B Cell ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tp53 Gene ◽  
Independent Prognostic Factor ◽  
High Grade ◽  
Tp53 Mutations

Abstract Background. TP53 mutations were described to have a negative impact on prognosis of patients with B-chronic lymphoid leukemia and diffuse large cell lymphoma. However, a role of TP53 mutations in high-grade B-cell lymphomas (HGL) is not well defined in context of other genetic aberrations. Materials and methods. 23 patients (7 males and 16 females) had diagnosis of HGL were treated in National Research Center for hematology, Moscow, Russia. Median age was 49 years old (30-76). 5 patients had HGL with c-MYC (MYC-R) and BCL2 genes rearrangements and 2 - HGB with MYC-R and BCL6 rearrangements. 17 (74%) patients had MYC-R, 11/23 (48%) had double expresser lymphoma (MYC≥40%, BCL2≥50%) (DE). Median of observation time was 29,1 months (6,3-99,8). 19 (82%) of patients had IPI score 3-5 points. 16 patients underwent LM-B-04 with rituximab (Table 1), 5 - R-(DA)-EPOCH, 2 - R-CHOP-21. In 5 cases autologous stem cell transplantation was performed. Sanger sequencing was performed to identify mutations in exons 5-8 of TP53 gene using DNA extracted from formalin fixed paraffin embedded tissue («Extra-DNA» kit, «Genetechnology» LLC). Primers to TP53 gene were synthesized based on nucleotide sequences data available online on website ncbi.com by «Evrogene». To evaluate an influence of such factors as TP53 mutation (TP53mut), MYC-R, DHL, DE, gender, therapy on overall survival (OS) and time to progression (TTP) were performed multivariate dispersion analysis and Cox regression analysis (STATISTICA 10). Results: 8 (35%) cases with TP53mut were identified: c.535C>T 45,6% p.H179Y, c.524G>C 15,6% p.R175P, c.743G>A 75,6% p.R247Q, c.487T>A 25,2% p.Y163N, c.824G>A 75% p.C275Y, c.713G>A 87,7% p.C238Y, c.745A>G 31,9% p.R249G, c.639A>G 41,8% p.R213R. 7/8 of them harbored MYC-R, 2/8 had DHL. In univariate (Picture 1, 2) and multivariate analysis pts harboring TP53mut had worse OS (median OS was 6,2 (0,7-9,5) vs 25,5 (0,7-99,8) months, p=0,004) and shorter TTP (median TTP 3,5 (0,7-9,5) vs 23,1 (0,7-99,8) months, p=0,027) than patients without TP53mut. DHL status had also an adverse effect on OS with lower significance than in pts with TP53mut (p=0,022). Adverse effect of TP53mut trends to play a role in combination with c-MYC gene rearrangement, thus5 pts TP53mut/MYC-R had shorter TTP than 5 DHL pts (3,4 (1,1-9,5) vs 7,3 (0,6-67,1) months, p=0,07). Conclusion: High-grade lymphoma has a more powerful and independent prognostic factor than double-hit status - TP53 mutation that contribute inferior prognosis. This factor shouldn't be underestimated in routine diagnostics because of its frequency and requirement of a different therapeutic approach. Disclosures No relevant conflicts of interest to declare.

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