Poor outcome in patients with diffuse large B-cell lymphoma is associated with high percentage of bcl-2 and Ki 67-positive tumor cells

Jovanović, Marina; Jaković, Ljubomir; Bogdanović, Andrija; Marković, Olivera; Martinović, Vesna Cemerikić; Mihaljević, Biljana

doi:10.2298/vsp0909738p

Cited by 15 publications

(7 citation statements)

References 25 publications

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“…However, we demonstrated a significant correlation between p16 hypermethylation and normal level of LDH and low/intermediate low IPI score. These two parameters have been related to better prognosis in many studies, which is confirmed for IPI in ours. To our knowledge, we are the first to detect such associations, so the importance of our results should be confirmed in the further studies on the larger number of samples.…”

Section: Discussionsupporting

confidence: 87%

Hypermethylation of p15 Gene in Diffuse – Large B‐Cell Lymphoma: Association with Less Aggressiveness of the Disease

Krajnović

Jovanovic

Mihaljević

et al. 2014

Clinical Translational Sci

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In this study, methylation-specifi c polymerase chain reaction was used to investigate the potential prognostic signifi cance of the methylation status of p15 , p16, MGMT , and DAPK genes in 51 specimens of diffuse large B-cell lymphoma (DLBCL). Hypermethylation of p15 gene was signifi cantly more prevalent in patients without relapse ( p = 0.001) and there was a trend toward more frequent presence of p15 methylation in patients without death outcome within 5-year follow-up period ( p = 0.086) Also, there was a trend toward accumulation of p15 methylation with favorable clinicopathological parameters including: age ≤ 60 years ( p = 0.091), normal levels of lactate dehydrogenase ( p = 0.090), Eastern Cooperative Oncology Group performance status < 2 ( p = 0.095), and low/intermediate low International Prognostic Index ( p = 0.076). In the female group and group of the patients without bulky tumor mass, treated with chemotherapeutic regimens including rituximab, methylation of p15 was signifi cantly related to longer overall survival ( p = 0.036 and 0.027, respectively). Our results suggest that promoter methylation of p15 gene could have prognostic value in DLBCL patients treated with rituximab when used in combination with gender and tumor size. Clin Trans Sci 2014; Volume 7: 384-390Keywords: diffuse large B-cell lymphoma , methylation, p15 , prognosis , rituximab 385 VOLUME 7 • ISSUE 5 WWW.CTSJOURNAL.COM Krajnović et al. ■ Hypermethylation of p15 Gene in DLBCL considered positive for Bcl-2, Bcl-6, or CD10 when at least 50%, 10%, or 20% of tumor cells expressed Bcl2, Bcl6, or CD10 protein, respectively. Expression of Ki67 protein in 0-30% of tumor cells was considered as weak, in 30-60% of tumor cells as moderate, and in more than 60% of the cells as strong. All procedures were carried out with the prior informed consent of the patients and with the approval of the local Ethic Committee. Treatment consisted of CHOP/R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab) regimen. Some patients had adjuvant radiotherapy and/or surgery, and some of them underwent autologous stem-cell transplantation. Response criteria and survival outcomes were defi ned according to the recommendation of Cheson et al. 17Analysis of methylation status of the p15 , p16 , MGMT , and DAPK genes DNA methylation patterns in the promoter CpG islands of the p15 , p16 , MGMT , and DAPK genes were determined in all of 51 samples by methylation-specifi c polymerase chain reaction (MSP) following the bisulfi te modifi cation of isolated genomic DNA, as described earlier.18 Briefl y, DNA was isolated from deparaffi ned tumor specimens using standard proteinase K, phenol/chloroform/isoamyl alcohol extraction, and ethanol precipitation.19 Two micrograms of isolated DNA were denatured by NaOH (fi nal 0.3 mol/L) at 42°C for 30 minutes and modifi ed by sodium bisulfi te (5.20-5.69 mol/L, pH 5.0, Sigma, St Louis, MO, USA) for 18 hours at 50°C . Aft er incubation, DNA was purifi ed using the DNA extraction...

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Section: Discussionsupporting

confidence: 87%

Hypermethylation of p15 Gene in Diffuse – Large B‐Cell Lymphoma: Association with Less Aggressiveness of the Disease

Krajnović

Jovanovic

Mihaljević

et al. 2014

Clinical Translational Sci

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“…The prognostic significance of Bcl-2 protein expression is controversial [5,6,7,8,9,10,13,19,20,26,27]. Some studies [8,9,10,20,27,28,30] showed that Bcl-2 protein overexpression was associated with poor OS, but some other studies [5,6,7,13,19,26] showed no difference in OS. Pervez et al reported positive Bcl-2 protein expression in 75 of 117 (64.1%) patients in their study on 117 patients with DLBCL.…”

Section: Discussionmentioning

confidence: 99%

“…Miller et al [32] reported that tumor proliferation of >80.0% was associated with poorer survival in previously untreated patients with aggressive NHL, whereas Hall et al [35] found that patients who responded well to chemotherapy were less likely to relapse if they had >80.0% tumor proliferation. Jovanovic et al reported that the patients with a high proliferative fraction (Ki67 > 60.0%) had a worse OS rate with log-rank test analysis [30]. Conversely, Hasselblom et al found that patients with low Ki67 expression (<49.0%) had significantly worse progression-free survival and OS as independent risk factors [36].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Bcl-2 and p53 Protein Expressions and Ki67 Proliferative Index in Diffuse Large B-cell Lymphoma

Kucukzeybek¹,

Bener²,

Çallı³

et al. 2013

Tjh

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Objective: Diffuse large B-cell lymphoma (DLBCL) is a high-grade neoplasm that has heterogeneous properties in clinical, morphological, and immunophenotypic aspects. In the present study the effects of p53, Bcl-2, and Ki67 on prognosis and their relationships with clinical parameters were examined.   Materials and Methods: Thirty-five patients who had been diagnosed with nodally located DLBCL at İzmir Atatürk Training and Research Hospital between January 1999 and June 2006 were included in the study. The Ann Arbor classification system was used to determine the stage of the patients. The patients were evaluated according to age, sex, stage, B symptoms, extranodal involvement, and lactate dehydrogenase (LDH) level as well as immunohistochemically. P53 protein and Bcl-2 oncoprotein expressions and Ki67 proliferation index were assessed immunohistochemically. Results: High Bcl-2 expression was found in 9 patients (25.7%), high p53 expression was found in 10 patients (28.6%), and high Ki67 was observed in 23 patients (65.7%). There was no significant correlation between p53 expression, Bcl-2 expression, or Ki67 proliferation index and age, sex, stage, B symptoms, extranodal involvement, LDH level, and overall survival (p>0.05). We did not find a relationship among p53 expression, Bcl-2 expression, Ki67 proliferation index, and prognosis (p>0.05). There was no significant relationship between overall survival and age, sex, stage, B symptoms, extranodal involvement, or LDH level (p>0.05). Our results revealed that Bcl-2 and p53 protein expressions and Ki67 proliferation index have no effect on overall survival of patients with DLBCL.Conclusion: The prognostic importance of p53 and Bcl-2 protein expressions and Ki67 proliferation index in DLBCL, which has biological and clinical heterogeneity, can be understood in a large series of studies that have subclasses and immunohistochemical markers with optimal cut-off values.

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“…The primary end point used in the determination of cutoff value was OS. Cut-off values for Bcl-2 was defined as 50% and Ki-67 was 75%, as was referred to the previous studies 26, 27.…”

Section: Methodsmentioning

confidence: 99%

EZH2/Bcl-2 Coexpression Predicts Worse Survival in Diffuse Large B-cell Lymphomas and Demonstrates Poor Efficacy to Rituximab in Localized Lesions

et al. 2019

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Enhancer of zeste homolog 2 (EZH2) and Bcl-2 gene rearrangement or protein upregulation played pivotal roles in the carcinogenesis of various malignancies including lymphomas. However, EZH2/Bcl-2 expression pattern and its clinicopathologic/prognostic significance in diffuse large B-cell lymphoma (DLBCL) remain unclear. To identify the association among EZH2, Bcl-2, clinicopathologic parametres in DLBCL, 2 DLBCL patient sets (test cohort, n=85; validation cohort n=51) and DLBCL cell lines were studied by tumor tissue microarray (TMA), immunohistochemistry and western blot. The optimal cut-off of EZH2 was determined by X-tile program from test cohort, as was verified in validation cohort. The prognostic significance was determined via Kaplan-Meier survival estimates and log-rank tests. Consequently, EZH2 and Bcl-2 expression were both enhanced and positively correlated with each other (𝑃=0.001) in both DLBCL patients and cell lines. EZH2/Bcl-2 coexpression was associated with poor overall survival (OS) and progression-free survival (PFS) in all DLBCL patients (all P <0.05). Univariate analyses revealed that EZH2/Bcl-2 coexpression correlated to worse objective response rate (ORR), shorter OS and PFS in DLBCL patients treated with RCHOP while multivariate analysis indicated that only elevated LDH level ( P =0.001) and presence of B symtom ( P =0.008) rather than EZH2/Bcl-2 coexpression were associated with worse OS. No survival benefit from rituximab regimen had been demonstrated in the early-staged DLBCL patients with EZH2/Bcl-2 coexpression. While in the subgroup of III-IV stage, RCHOP regimen showed obvious better OS and PFS than CHOP ( P =0.039 and 0.005). In conclusion, EZH2/Bcl-2 coexpression defines unrecognized subgroup of DLBCL patients with distinct epigenetic phenotype and worse outcome.

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Poor outcome in patients with diffuse large B-cell lymphoma is associated with high percentage of bcl-2 and Ki 67-positive tumor cells

Abstract: An initial high IPI score associated with high Ki-67+ and bcl2+ could represent possible predictive factors of poor prognosis, which would help to identify a high risk subgroup of newly diagnosed DLBCL.

Cited by 15 publications

References 25 publications

Hypermethylation of p15 Gene in Diffuse – Large B‐Cell Lymphoma: Association with Less Aggressiveness of the Disease

Hypermethylation of p15 Gene in Diffuse – Large B‐Cell Lymphoma: Association with Less Aggressiveness of the Disease

Prognostic Significance of Bcl-2 and p53 Protein Expressions and Ki67 Proliferative Index in Diffuse Large B-cell Lymphoma

EZH2/Bcl-2 Coexpression Predicts Worse Survival in Diffuse Large B-cell Lymphomas and Demonstrates Poor Efficacy to Rituximab in Localized Lesions

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