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.

scholarly journals Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma

2017 ◽  
Vol 92 (7) ◽  
pp. 689-694 ◽  
Author(s):  
Eileen Wedge ◽  
Jakob Werner Hansen ◽  
Christian Garde ◽  
Fazila Asmar ◽  
Dorte Tholstrup ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Independent Prognostic Factor ◽  
Large B Cell Lymphoma ◽  
Global Hypomethylation ◽  
Large B Cell

scholarly journals Increased MYC copy number is an independent prognostic factor in patients with diffuse large B-cell lymphoma

2017 ◽  
Vol 30 (12) ◽  
pp. 1688-1697 ◽  
Author(s):  
Andrés E Quesada ◽  
L Jeffrey Medeiros ◽  
Parth A Desai ◽  
Pei Lin ◽  
Jason R Westin ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
B Cell ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Independent Prognostic Factor ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Sarcopenia is an independent prognostic factor in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy

2013 ◽  
Vol 55 (4) ◽  
pp. 817-823 ◽  
Author(s):  
Hélène Lanic ◽  
Jerôme Kraut-Tauzia ◽  
Romain Modzelewski ◽  
Florian Clatot ◽  
Sylvain Mareschal ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Elderly Patients ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Independent Prognostic Factor ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Sequential Time-Point Mutational Analysis of TP53 in Follicular Lymphoma Undergoing Transformation to Large B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1361-1361
Author(s):  
Andrew J. Davies ◽  
Abigail M. Lee ◽  
Claire Taylor ◽  
Andrew J. Clear ◽  
Lindsey K. Goff ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mutation Status ◽  
Tp53 Mutations ◽  
Large B Cell Lymphoma ◽  
Mdm2 Expression ◽  
Large B Cell

Abstract Transformation of follicular lymphoma (FL) to a more aggressive clinical and histological phenotype, typically diffuse large B-cell lymphoma (DLBCL), occurs frequently. It is associated with a number of recurrent genomic insults, including the acquisition of TP53 mutations in a subset of patients (pts). The use of novel agents targeting p53 and mdm2 appears attractive given the resistance of transformed DLBCL to conventional therapies. Tailoring these therapies will require precise characterisation of mutation status and functional consequence in transformation. The frequency and temporal relationship of TP53 mutation gain to transformation was analysed in DNA from sequentially collated lymph node biopsies taken pre and post transformation (n=91) obtained from 29 pts. A median of 3 samples (range 2–5) was available from each pt (13 taken at FL presentation). Transformation was documented a median of 3.8 years (range 0.2 to 15.2) from diagnosis, and median follow up from diagnosis for all pts at the time of analysis was 6.7 years (range 2 to 19.1). The entire coding sequence of TP53 was screened by PCR, fluorescent-SSCP and sequencing. Loss of heterozygosity (LOH) was examined at 5 common polymorphic sites with in TP53. Immunocytochemistry for p53, mdm2 and p21 was performed on slides obtained from 77 available paraffin blocks. Ten mutations were detected in 8 pts (28%), of which 5 were missense. The remaining was accounted for by two nonsense mutations, a splice mutation, a branch site mutation and a single base insertion. All mutations were within the genomic region covered by primer sets exon 5–7 inclusive. Mutated TP53 was first documented only at the time of histologic transformation in 4 pts, in the remainder latency between documentation in FL sample and transformation was variable (0.5–6 years). For pts with mutations, time from documentation to death ranged from 1 month-12 years (median 37 months), with 2 pts alive 8.5 and 13.5 years following initial documentation. LOH occurred in 2 pts, both at the time of transformation and was associated with short survival (1 and 17 months). Overall survival from diagnosis or histological transformation was not significantly different between pts with mutated TP53 and wtTP53. Five TP53 mutated pts. recurred post transformation (either with FL or DLBCL); in 4 pts the identical mutation was detected at this time. p53 staining was positive in 82% (9/11) of biopsies with missense mutations, and negative in 71% (45/63) with wtTP53. Mdm2 expression was predominantly centroblastic in FL and was correspondingly higher in DLBCL samples (mean 72%; 95% CI 68–76%) compared to FL (mean 58%; 95% confidence interval: 54–62%) (p<0.001). Mdm2 expression did not correlate with TP53 mutation status. Expression of p21 antigen was positive in 19/71 (27%) cases and did not correlate with histology. Absence of p21 occurred in both wtTP53 (66%) and mutated TP53 (94%) samples. TP53 mutations were associated with transformation in only a subset of pts; the potential of individual mutations to induce phenotypic change was variable and thus may influence the potential success of novel TP53 directed therapies.

TP53 Mutation Is an Independent Predictor of Poor Survival in Untreated Patients with CD20+ Aggressive B-Cell Lymphoma: Analysis within the Ricover-60 Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 546-546
Author(s):  
Thorsten Zenz ◽  
Markus Kreuz ◽  
Doris Winter ◽  
Hanne Helfrich ◽  
Maxi Fuge ◽  
...  
Keyword(s):  
B Cell ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
Independent Predictor ◽  
B Cell Lymphoma ◽  
Event Free Survival ◽  
Risk Models ◽  
Free Survival ◽  
Tp53 Mutations ◽  
Aggressive B Cell Lymphoma

Abstract Abstract 546 TP53 is commonly mutated across lymphoma entities. TP53 mutations have been found in 20–25 % of aggressive B-cell lymphomas and most studies suggest an impact on outcome. Few studies have addressed the impact of TP53 mutations in larger trial cohorts. In order to evaluate the contribution of TP53 mutation status to current risk models, we investigated TP53 gene mutations within the RICOVER-60 trial of the DSHNHL. Of 1222 elderly patients (aged 61–80 years) randomly assigned to six or eight cycles of CHOP-14 with or without Rituximab, 265 patients (representative of the whole cohort) were analyzed for TP53 mutations. Genomic DNA samples extracted from paraffin embedded tissue were used and mutations were studied by Sanger sequencing of exons 4–9. All patients had untreated CD20+ aggressive B-cell lymphoma according to the World Health Organization classification as confirmed by reference pathology. The primary endpoint of the trial was event-free survival. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website (NCT00052936). TP53 mutations were demonstrated in 64 of 265 patients (24.1%). The incidence is in accordance to prior studies. TP53 mutation was associated with higher LDH (66% vs. 37%), higher IPI-Scores (IPI 4/5 27% vs. 12%), and B-symptoms (41% vs. 24%) (TP53 mutant (mut) and wild type (wt) groups resp.). Patients with TP53 mutation were less likely to obtain a CR/Cru 62.5% (mut.) vs. 79.6% (wt). The median observation time was 40.2 months and the presence of TP53 mutations was associated with decreased OS; EFS and PFS. The respective 3 year overall and event-free survival were 49% (vs. 77%) and 41% (vs. 60.5%) for the group with TP53 mutation (p<0.0001; <0.01). The analysis of the TP53 mutant subgroup (n=64) showed no impact of the treatment arm (R-CHOP vs. CHOP; 6 vs. 8 cycles) for OS, EFS or PFS in univariate analysis. In a Cox proportional hazard models including the IPI, ECOG, LDH, stage and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.1) and most importantly OS (HR 2.4; p<0.001). Additional factors associated with EFS were LDH, ECOG, stage and Rituximab arm. Our findings suggest that TP53 mutations are independent predictors of poor PFS, EFS and OS in untreated patients with aggressive CD20+ lymphoma. Based on the analysis within a homogenous trial cohort, strategies to improve outcome for the 20–25% of patients with mutant p53 should be developed. Recurrent genetic lesions should be integrated into risk models in DLBCL. Fig.: Overall survival and TP53 mutation in aggressive B-NHL Fig.:. Overall survival and TP53 mutation in aggressive B-NHL Disclosures: No relevant conflicts of interest to declare.

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