Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study.

1996 ◽  
Vol 14 (7) ◽  
pp. 2131-2138 ◽  
Author(s):  
M H Kramer ◽  
J Hermans ◽  
J Parker ◽  
A D Krol ◽  
J C Kluin-Nelemans ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Lymphoma ◽  
P53 Protein ◽  
B Cell Lymphoma ◽  
Population Based ◽  
Clinical Factors ◽  
P53 Expression ◽  
P53 Protein Expression ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein

PURPOSE We studied the prognostic significance of bcl2 and p53 protein expression in relation to clinical and pathologic characteristics in patients with diffuse large B-cell lymphoma (LCL). PATIENTS AND METHODS Three hundred seventy-two patients with LCL were retrieved from a population-based registry for non-Hodgkin's lymphoma (NHL). bcl2 and p53 protein expression was studied on paraffin-embedded tumor tissue by immunohistochemistry in relation to clinical factors. Response to therapy and survival were analyzed in 165 patients who were uniformly staged and treated and for whom all prognostic data were available according to the International Prognostic Index (IPI). RESULTS Forty-five percent of tumors showed strong expression of the bcl2 protein (bcl2++), with a higher frequency in patients with primary nodal involvement. Disease-free survival (DFS) was significantly better in bcl2-negative/intermediate (bcl2-/+) cases as compared with bcl2++ cases (P = .0011). At 5 years, bcl2-/+ patients showed a DFS rate of 74%, in contrast to bcl2++ patients with a DFS rate of 41% (P = .002). Bcl2 was the strongest independent prognostic value in a multivariate analysis, with a relative risk (RR) of 3.0 in comparison to p53 expression and the clinical factors of the IPI. Overall survival (OS) was not significantly influenced by bcl2 protein expression. p53 protein expression was found in 13% of cases, with a higher frequency in patients with extensive disease. p53 expression did not influence the chance to achieve complete remission (CR) and survival. CONCLUSION bcl2 protein is frequently expressed in LCL and is a strong independent prognostic factor for DFS. p53 expression is related with high tumor burden, but is not an independent risk factor for CR and survival.

scholarly journals Concurrent Expression of MYC and BCL2 in Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

2012 ◽  
Vol 30 (28) ◽  
pp. 3452-3459 ◽  
Author(s):  
Nathalie A. Johnson ◽  
Graham W. Slack ◽  
Kerry J. Savage ◽  
Joseph M. Connors ◽  
Susana Ben-Neriah ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
Molecular Subtype ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Large B Cell

Purpose Diffuse large B-cell lymphoma (DLBCL) is curable in 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MYC translocations, with or without BCL2 translocations, have been associated with inferior survival in DLBCL. We investigated whether expression of MYC protein, with or without BCL2 protein expression, could risk-stratify patients at diagnosis. Patients and Methods We determined the correlation between presence of MYC and BCL2 proteins by immunohistochemistry (IHC) with survival in two independent cohorts of patients with DLBCL treated with R-CHOP. We further determined if MYC protein expression correlated with high MYC mRNA and/or presence of MYC translocation. Results In the training cohort (n = 167), MYC and BCL2 proteins were detected in 29% and 44% of patients, respectively. Concurrent expression (MYC positive/BCL2 positive) was present in 21% of patients. MYC protein correlated with presence of high MYC mRNA and MYC translocation (both P < .001), but the latter was less frequent (both 11%). MYC protein expression was only associated with inferior overall and progression-free survival when BCL2 protein was coexpressed (P < .001). Importantly, the poor prognostic effect of MYC positive/BCL2 positive was validated in an independent cohort of 140 patients with DLBCL and remained significant (P < .05) after adjusting for presence of high-risk features in a multivariable model that included elevated international prognostic index score, activated B-cell molecular subtype, and presence of concurrent MYC and BCL2 translocations. Conclusion Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.

scholarly journals The Prognostic Value of MYC, BCL2 and BCL6 Translocations and Protein Expressions in Young Patients with High-Risk Diffuse Large B-Cell Lymphoma Treated with R-CHOEP

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1694-1694
Author(s):  
Mette Ølgod Pedersen ◽  
Anne Ortved Gang ◽  
Estrid Hoegdall ◽  
Helle Knudsen ◽  
Anne F. Lauritzen ◽  
...  
Keyword(s):  
High Risk ◽  
Protein Expression ◽  
Prognostic Value ◽  
Prognostic Markers ◽  
Cell Lymphoma ◽  
Young Patients ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Bcl2 Expression

Abstract Background: In young patients with high-risk diffuse large B-cell lymphoma (DLBCL) treatment with R-CHOEP (R-CHOP + etoposide) has been associated with improved outcome. Whether established prognostic markers in R-CHOP treated patients are prognostic in R-CHOEP treated patients remain to be investigated. In addition predictive markers for response to R-CHOEP need to be investigated. Methods: A Danish population based cohort of 140 young (age 18-60) patients with high-risk (2 ≥ additional risk factors including advanced stage, elevated s-LDH, and performance status >1) primary DLBCL diagnosed between 2004 and 2008 was investigated. Patients were treated with R-CHOP (n=84) or R-CHOEP (n=56). Formalin fixed paraffin embedded tumor tissue specimens were analysed for MYC-, BCL2- and BCL6- protein expression by semiquantitative immunohistochemistry (IHC) and genetic translocations by Fluorescence In Situ Hybridization (FISH). Results: MYC protein expression ≥ 40% was seen in 67/106 patients (71%), BCL2 protein expression > 0 and BCL2 protein expression ≥ 70% was seen in 106/138 (77%) and 81/117 patients (69%) respectively. BCL6 expression ≥ 30% was seen in 96/114 patients (84%). Concurrent expression of MYC≥40% and BCL2≥70% (IHC double hit (DH)) was seen in 50/106 patients (47%). Concurrent MYC≥40%, BCL2 >0 or BCL6<30% (Triple hit (TH) score score 2-3) was seen in 61/103 patients (59%). MYC, BCL2 and BCL6 translocation was seen in 14/104 (13%), 31/104 (30%) and 27/104 (26%) patients respectively. Concurrent MYC BCL2/BCL6 translocation (DH) was seen in 8/102 (8%) patients. MYC over-expression was not associated with reduced progression free survival (PFS) in either R-CHOP or R-CHOEP treated patients. BCL2 expression (>0%) and BCL2 overexpression (≥70%) was associated with reduced PFS in R-CHOP (HR: 0.3; 95%CI:0.1-0.9; p=0.03 and HR: 0.4; 95%CI: 0.2-0.9; p=0.02) - but not in R-CHOEP treated patients (HR: 0.9; 95%CI:0.3-3.2; p=0.9 and HR: 0.5; 95%CI: 0.1-1.9; p=0.3). IHC DH was associated with a trend towards reduced PFS in R-CHOP - but not in R-CHOEP treated patients (HR: 0.6; 95%CI:0.3-1.1; p=0.08 and HR: 1.2; 95%CI: 0.4-4.0; p=0.7 respectively). TH score 2-3 was associated with reduced PFS in R-CHOP - but not in R-CHOEP treated patients (HR: 0.4; 95%CI:0.2-0.9; p=0.015 and HR: 0.8; 95%CI: 0.2-2.8; p=0.74). There was no statistical significant interaction between treatment modality and BCL2 expression, IHC DH or TH score 2-3. MYC, BCL2 and BCL6 translocations were not prognostic markers with respect to PFS in either R-CHOP or R-CHOP treated patients. DH translocations were too few to perform meaningful statistical analyses. Conclusions: BCL2 expression, IHC DH and TH score 2-3 had prognostic value in R-CHOP treated patients but this was not seen in R-CHOEP treated patients in this study suggesting the need for novel prognostic markers in R-CHOEP treated patients. Neither BCL2 expression, IHC DH nor TH score 2-3 were however predictive markers for response to treatment with R-CHOEP in this cohort of patients. This could possibly be due to the limited number of patients investigated. MYC BCL2/BCL6 DH translocations were too few to perform meaningful statistical analyses and whether DH translocation will retain a prognostic value in R-CHOEP treated patients also remains to be investigated in larger patient cohorts. A possible predictive value of DH translocation also needs further investigation. Disclosures No relevant conflicts of interest to declare.

Clinical Relevance of BCL2, BCL6, and MYC Rearrangements in Diffuse Large B-Cell Lymphoma

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3152-3162 ◽  
Author(s):  
M.H.H. Kramer ◽  
J. Hermans ◽  
E. Wijburg ◽  
K. Philippo ◽  
E. Geelen ◽  
...  
Keyword(s):  
Complete Remission ◽  
Protein Expression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Disease Stage ◽  
Clinical Heterogeneity ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Extranodal Lymphomas ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLCL) is characterized by a marked degree of morphologic and clinical heterogeneity. We studied 156 patients with de novo DLCL for rearrangements of the BCL2, BCL6, and MYC oncogenes by Southern blot analysis and BCL2 protein expression. We related these data to the primary site of presentation, disease stage, and other clinical risk factors. Structural alterations of BCL2, BCL6, and MYC were detected in 25 of 156, 36 of 116, and 10 of 151 patients, respectively. Three cases showed a combination of BCL2 and BCL6 rearrangements, and two cases had a combination of BCL6 and MYC rearrangements. BCL2 rearrangement was found more often in extensive (39%) and primary nodal (17%) lymphomas than in extranodal cases (4%) (P = .003). BCL2 rearrangement was present in none of 40 patients with stage I disease, but in 22% of patients with stage II to IV (P = .006). The presence of BCL2 rearrangements did not significantly affect overall survival (OS) or disease-free survival (DFS). In contrast, high BCL2 protein expression adversely affected both OS (P = .008) and DFS (P = .01). BCL2 protein expression was poorly correlated with BCL2 rearrangement: only 52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases had high BCL2 protein expression. Rearrangement of BCL6 was found more often in patients with extranodal (36%) and extensive (39%) presentation versus primary nodal disease (28%). No significant correlation was found with disease stage, lymphadenopathy, or bone marrow involvement. DFS and OS were not influenced by BCL6 rearrangements. MYC rearrangements were found in 16% of primary extranodal lymphomas, versus 2% of primary nodal cases (P = .02). In particular, gastrointestinal (GI) lymphomas (5 of 18 cases, 28%) were affected by MYC rearrangements. The distinct biologic behavior of these extranodal lymphomas was reflected by a high complete remission (CR) rate: 7 of 10 patients with MYC rearrangement attained complete remission and 6 responders remained alive for more than 4 years, resulting in a trend for better DFS (P = .07). These data show the complex nature of molecular events in DLCL, which is a reflection of the morphologic and clinical heterogeneity of these lymphomas. However, thus far, these genetic rearrangements fail as prognostic markers. © 1998 by The American Society of Hematology.

Outcomes of diffuse large b-cell lymphoma with MYC and/or BCL2 protein expression treated with intensive chemotherapy.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 7563-7563
Author(s):  
Amir Issa ◽  
Vishwanath Sathyanarayanan ◽  
Michelle A. Fanale ◽  
Yasuhiro Oki ◽  
Fredrick B. Hagemeister ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Large B Cell

The t(14;18)(q32;q21) Characterizes a Subset of Patients with Diffuse Large-B Cell Lymphoma of Germinal Center Origin with Poor Outcome: Report From the International DLBCL Rituximab-CHOP Consortium Program Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 949-949 ◽  
Author(s):  
Carlo Visco ◽  
Alexander Tzankov ◽  
Zijun Y. Xu-Monette ◽  
Roberto N. Miranda ◽  
Emanuele S. G. d'Amore ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Individual Risk ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Large B Cell

Abstract Abstract 949 Introduction: Diffuse large B cell lymphoma (DLBCL) has a highly variable outcome, and individual risk assessment is largely based on clinical features. Gene expression profiling (GEP) stratifies patients into those with germinal center B-cell (GCB) and activated B-cell subtype (ABC) subtype with different prognoses. These groups have been shown to predict prognosis in patients treated with CHOP or R-CHOP. Conversely, the role of other recognized prognostic markers, such as BCL2 gene abnormalities or Bcl2 expression has been questioned in the new therapeutic era. Materials and Methods: In 438 patients treated with R-CHOP for de novo DLBCL, we analyzed the tumors by immunohistochemistry for Bcl2 protein expression and by interphase fluorescence in situ hybridization (FISH) for BCL2 translocation and other abnormalities. All cases were successfully studied by GEP. The cutoff for Bcl2 protein expression, 60%, used as prognostic factor was determined using receiver operating characteristic curves. Progression-free survival (PFS) and overall survival (OS) were assessed. Results: The t(14;18)(q32;q21) was detected in 82 cases (18.7%) and BCL2 gains occurred in 63 cases (14.3%). Both t(14;18) and BCL2 gains strongly correlated with higher levels of Bcl2 protein expression (p<0.0001 for both). Presence of t(14;18) was associated with the GCB subtype (p<0.0001), whereas BCL2 gains were associated with the ABC subtype (p=0.004). BCL2 gains were not predictive of PFS in any patients' subgroups. Conversely, within the GCB subtype, patients with the t(14;18) displayed a significantly worse outcome compared to GCB patients without t(14;18) with a 5-year PFS of 45% vs 68%, respectively (p<0.0001). Outcome of patients with DLBCL associated with t(14;18) was similar to patients with the ABC subtype (45% vs 48%, p=0.30, Figure 1). No impact of the t(14;18) and BCL2 gains was observed on patients with ABC-DLBCL. Using immunohistochemistry, patients with Bcl2 positive (>60%) tumors had significantly inferior PFS in the GCB subgroup (p=0.03), but not in the ABC subgroup (p=0.54). Multivariate analysis revealed that the presence of the t(14;18), but not Bcl2 protein expression, was independent of the International Prognostic Index in predicting outcome of our patients. Conclusions: Patients with the GCB subtype and t(14;18) exhibit a significantly worse prognosis than patients without t(14;18) when treated with R-CHOP. The assessment of t(14;18) by FISH approach not only functions as a valuable prognosticator for individual risk estimation in GCB-DLBCL patients in addition to the established parameters, but also provides valuable result for therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

BCL2 gene aberration as an IPI-independent marker for poor outcome in non-germinal-centre diffuse large B cell lymphoma

2009 ◽  
Vol 62 (10) ◽  
pp. 903-907 ◽  
Author(s):  
E C Obermann ◽  
M Csato ◽  
S Dirnhofer ◽  
A Tzankov
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Germinal Centre ◽  
Individual Risk ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Worse Prognosis ◽  
Large B Cell

Aim:Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in the western hemisphere, and is characterised by a highly variable outcome that impedes individual risk assessment. Lacking reliable biomarkers, the international prognostic index (IPI) has been the most reliable factor to predict survival and stratify patients for therapy. The aim of this study was to investigate the frequency and potential prognostic role of BCL2 aberrations on the chromosomal level and the protein level in a large DLBCL collective.Methods:Fluorescence in situ hybridisation (FISH) with commercially available dual-colour break-apart probes and immunohistochemistry were used to assess BCL2 gene abnormalities and bcl2 protein expression on validated tissue microarrays containing 224 well-characterised cases of primary DLBCL.Results:FISH analysis of BCL2 revealed a break in 40/215 cases (19%) and a gain in 66/171 (39%) cases. Only BCL2 gains correlated with bcl2 protein expression (p = 0.001). Presence of any BCL2 gene abnormality, particularly gains, correlated independently of the IPI with a significantly worse prognosis in DLBCL of non-germinal centre (non-GC) phenotype as opposed to DLBCL of non-GC type without this genetic alteration (p = 0.003). DLBCL of germinal centre phenotype did not show this association.Conclusions:Cases of DLBCL of the non-GC type with BCL2 gene aberration are accompanied by a significantly worse prognosis as opposed to cases without such gene abnormalities. It may be helpful to asses BCL2 gene abnormalities by FISH in addition to assessing established parameters for individual risk estimation in DLBCL.

scholarly journals MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab

2014 ◽  
Vol 165 (3) ◽  
pp. 382-391 ◽  
Author(s):  
Anamarija M. Perry ◽  
Yuridia Alvarado-Bernal ◽  
Javier A. Laurini ◽  
Lynette M. Smith ◽  
Graham W. Slack ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Large B Cell

Clinical Relevance of BCL2, BCL6, and MYC Rearrangements in Diffuse Large B-Cell Lymphoma

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3152-3162 ◽  
Author(s):  
M.H.H. Kramer ◽  
J. Hermans ◽  
E. Wijburg ◽  
K. Philippo ◽  
E. Geelen ◽  
...  
Keyword(s):  
Complete Remission ◽  
Protein Expression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Disease Stage ◽  
Clinical Heterogeneity ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Extranodal Lymphomas ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLCL) is characterized by a marked degree of morphologic and clinical heterogeneity. We studied 156 patients with de novo DLCL for rearrangements of the BCL2, BCL6, and MYC oncogenes by Southern blot analysis and BCL2 protein expression. We related these data to the primary site of presentation, disease stage, and other clinical risk factors. Structural alterations of BCL2, BCL6, and MYC were detected in 25 of 156, 36 of 116, and 10 of 151 patients, respectively. Three cases showed a combination of BCL2 and BCL6 rearrangements, and two cases had a combination of BCL6 and MYC rearrangements. BCL2 rearrangement was found more often in extensive (39%) and primary nodal (17%) lymphomas than in extranodal cases (4%) (P = .003). BCL2 rearrangement was present in none of 40 patients with stage I disease, but in 22% of patients with stage II to IV (P = .006). The presence of BCL2 rearrangements did not significantly affect overall survival (OS) or disease-free survival (DFS). In contrast, high BCL2 protein expression adversely affected both OS (P = .008) and DFS (P = .01). BCL2 protein expression was poorly correlated with BCL2 rearrangement: only 52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases had high BCL2 protein expression. Rearrangement of BCL6 was found more often in patients with extranodal (36%) and extensive (39%) presentation versus primary nodal disease (28%). No significant correlation was found with disease stage, lymphadenopathy, or bone marrow involvement. DFS and OS were not influenced by BCL6 rearrangements. MYC rearrangements were found in 16% of primary extranodal lymphomas, versus 2% of primary nodal cases (P = .02). In particular, gastrointestinal (GI) lymphomas (5 of 18 cases, 28%) were affected by MYC rearrangements. The distinct biologic behavior of these extranodal lymphomas was reflected by a high complete remission (CR) rate: 7 of 10 patients with MYC rearrangement attained complete remission and 6 responders remained alive for more than 4 years, resulting in a trend for better DFS (P = .07). These data show the complex nature of molecular events in DLCL, which is a reflection of the morphologic and clinical heterogeneity of these lymphomas. However, thus far, these genetic rearrangements fail as prognostic markers. © 1998 by The American Society of Hematology.

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