Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is characterized by a marked degree of morphologic and clinical heterogeneity. Establishment of parameters that can predict outcome could help to identify patients who may benefit from risk-adjusted therapies. BCL-6 is a proto-oncogene commonly implicated in DLBCL pathogenesis. A real-time reverse transcription–polymerase chain reaction assay was established for accurate and reproducible determination of BCL-6 mRNA expression. The method was applied to evaluate the prognostic significance ofBCL-6 expression in DLBCL. BCL-6 mRNA expression was assessed in tumor specimens obtained at the time of diagnosis from 22 patients with primary DLBCL. All patients were subsequently treated with anthracycline-based chemotherapy regimens. These patients could be divided into 2 DLBCL subgroups, one with high BCL-6 gene expression whose median overall survival (OS) time was 171 months and the other with low BCL-6 gene expression whose median OS was 24 months (P = .007). BCL-6 gene expression also predicted OS in an independent validation set of 39 patients with primary DLBCL (P = .01). BCL-6 protein expression, assessed by immunohistochemistry, also predicted longer OS in patients with DLBCL. BCL-6 gene expression was an independent survival predicting factor in multivariate analysis together with the elements of the International Prognostic Index (IPI) (P = .038). By contrast, the aggregate IPI score did not add further prognostic information to the patients' stratification byBCL-6 gene expression. High BCL-6 mRNA expression should be considered a new favorable prognostic factor in DLBCL and should be used in the stratification and the design of risk-adjusted therapies for patients with DLBCL.

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An NCCN-IPI based immune-related gene prognostic model for diffuse large B-cell lymphoma

10.1101/2021.03.03.433839 ◽

2021 ◽

Author(s):

Shidai Mu ◽

Deyao Shi ◽

Lisha Ai ◽

Fengjuan Fan ◽

Fei Peng ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Prognostic Model ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Risk Patients ◽

Large B Cell

AbstractBackgroundAn enhanced International Prognostic Index (NCCN-IPI) was built to better discriminate diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. However, there is an urgent need to identify novel valuable biomarkers in the context of targeted therapies, such as immune checkpoint blockade (ICB) therapy.MethodsGene expression data and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. 73 immune-related hub genes in DLBCL patients with different IPI levels were identified by weighted gene co-expression network analysis (WGCNA), and 4 genes were selected to construct an IPI-based immune-related prognostic model (IPI-IPM). Afterward, the genetic, somatic mutational and molecular profiles of IPI-IPM subgroups were analyzed, as well as the potential clinical response of ICB in different IPI-IPM subgroups.ResultsThe IPI-IPM was constructed base on the expression of LCN2, CD5L, NLRP11 and SERPINB2, where high-risk patients had shorter overall survival (OS) than low-risk patients, consistent with the results in the GEO cohorts. The comprehensive results showed that a high IPI-IPM risk score was correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, high infiltration of CD8+ T cells and macrophages (M1, M2), as well as up-regulation of inhibitory immune checkpoints including PD-L1, LAG3 and BTLA, indicating more potential response to ICB therapy.ConclusionThe IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms on tumor progression and drug resistance, also sheds a light on developing immunotherapy for DLBCL.

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Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma

Blood ◽

10.1182/blood-2007-02-072082 ◽

2007 ◽

Vol 110 (13) ◽

pp. 4396-4405 ◽

Cited By ~ 64

Author(s):

Ken H. Young ◽

Dennis D. Weisenburger ◽

Bhavana J. Dave ◽

Lynette Smith ◽

Warren Sanger ◽

...

Keyword(s):

Gene Expression ◽

Dna Binding ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Poor Survival ◽

Large B Cell Lymphoma ◽

Large B Cell

Mutations of the TP53 tumor suppressor gene have been associated with poor survival in some series of diffuse large B-cell lymphoma (DLBCL) but not in other studies. The purpose of this study was to identify the frequency of TP53 alterations (mutations or deletions), characterize the gene expression of mutant/deleted cases, and determine the effects of mutations on survival. In a series of DLBCL that had previous gene expression profiling, we identified 24 mutations in 113 cases (21%). There was no difference in the frequency of mutations in the molecular subgroups of DLBCL. Twelve (50%) of the 24 cases had mutations localized to the DNA-binding codons in the core domain of TP53. The presence of any TP53 mutation correlated with poor overall survival (OS; P = .044), but DNA-binding mutations were the most significant predictor of poor OS (P < .001). Multivariate analysis confirmed that the International Prognostic Index, tumor size, and TP53 DNA-binding mutations were independent predictors of OS. Gene expression analysis showed that TRAILreceptor-2 (DR5) was the most differentially underexpressed gene in the TP53 mutated cases. Investigation is warranted into targeted therapy toward TRAIL receptor-2, to potentially bypass the adverse effect of mutated TP53 in DLBCL.

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A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma

Blood ◽

10.1182/blood-2012-05-430389 ◽

2012 ◽

Vol 120 (11) ◽

pp. 2290-2296 ◽

Cited By ~ 39

Author(s):

Anamarija M. Perry ◽

Teresa M. Cardesa-Salzmann ◽

Paul N. Meyer ◽

Luis Colomo ◽

Lynette M. Smith ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Expression Profiling ◽

Prognostic Model ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Biologic factors that predict the survival of patients with a diffuse large B-cell lymphoma, such as cell of origin and stromal signatures, have been discovered by gene expression profiling. We attempted to simulate these gene expression profiling findings and create a new biologic prognostic model based on immunohistochemistry. We studied 199 patients (125 in the training set, 74 in the validation set) with de novo diffuse large B-cell lymphoma treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies, and immunohistochemical stains were performed on paraffin-embedded tissue microarrays. In the model, 1 point was awarded for each adverse prognostic factor: nongerminal center B cell–like subtype, SPARC (secreted protein, acidic, and rich in cysteine) < 5%, and microvascular density quartile 4. The model using these 3 biologic markers was highly predictive of overall survival and event-free survival in multivariate analysis after adjusting for the International Prognostic Index in both the training and validation sets. This new model delineates 2 groups of patients, 1 with a low biologic score (0-1) and good survival and the other with a high score (2-3) and poor survival. This new biologic prognostic model could be used with the International Prognostic Index to stratify patients for novel or risk-adapted therapies.

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Clinical Features and Prognostic Significance of NOTCH1 Mutations in Diffuse Large B-Cell Lymphoma

Frontiers in Oncology ◽

10.3389/fonc.2021.746577 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhongqi Li ◽

Fang Yu ◽

Wenle Ye ◽

Liping Mao ◽

Jiansong Huang ◽

...

Keyword(s):

B Cell ◽

Clinical Features ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Significance ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of large lymphoid B cell malignancy with distinct clinical and genetic features. Recently, NOTCH1 mutations were identified in DLBCL cases by Next-generation sequencing (NGS), but the clinical features and prognostic impact were not systematically studied. Here, NOTCH1 genes in 161 DLBCL samples were sequenced by NGS. The prognostic value of NOTCH1 mutations was assessed in the context of clinical and laboratory factors, such as international prognostic index (IPI), cell-of-origin classification, double expression of BCL2 and c-MYC. The combined data from three Western cohorts were used to validate these results. As a result, NOTCH1 mutations were found in 17(10.6%) patients, and three patients had a hotspot mutation of c.7541_7542delCT. The presence of NOTCH1 mutations was significantly associated with poor complete response and progression free survival(PFS), which was independent of established clinical and laboratory parameters. In addition, 30 (1.92%) of 1562 patients treated with R-CHOP regimen in those combined Western cohorts had NOTCH1 mutations. Meta-analysis of the Western cohorts confirmed that NOTCH1 mutations were also associated with poor PFS and OS. In conclusion, DLBCL patients with the NOTCH1 mutations have worse PFS and OS, and the NOTCH1 mutations can be used as an independent predictor for patients with DLBCL.

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Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium

Blood ◽

10.1182/blood-2011-04-345256 ◽

2011 ◽

Vol 117 (26) ◽

pp. 7070-7078 ◽

Cited By ~ 121

Author(s):

Gilles Salles ◽

Daphne de Jong ◽

Wanling Xie ◽

Andreas Rosenwald ◽

Mukesh Chhanabhai ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Significance ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Cut Points ◽

Large B Cell Lymphoma ◽

Hla Dr ◽

Large B Cell

The Lunenburg Lymphoma Biomarker Consortium (LLBC) evaluated the prognostic value of IHC biomarkers in a large series of patients with diffuse large B-cell lymphoma (DLBCL). Clinical data and tumor samples were retrieved from 12 studies from Europe and North America, with patients treated before or after the rituximab era. Using tissue microarrays from 1514 patients, IHC for BCL2, BCL6, CD5, CD10, MUM1, Ki67, and HLA-DR was performed and scored according to previously validated protocols. Optimal cut points predicting overall survival of patients treated in the rituximab era could only be determined for CD5 (P = .003) and Ki67 (P = .02), whereas such cut points for BCL2, BCL6, HLA-DR, and MUM1 could only be defined in patients not receiving rituximab. A prognostic model for patients treated in the rituximab era identified 4 risk groups using BCL2, Ki67, and International Prognostic Index (IPI) with improved discrimination of low-risk patients. Newly recognized correlations between specific biomarkers and IPI highlight the importance of carefully controlling for clinical and biologic factors in prognostic models. These data demonstrate that the IPI remains the best available index in patients with DLBCL treated with rituximab and chemotherapy.

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Gene Expression Profile Associated with Survival in Patients with Diffuse Large B-Cell Lymphoma Treated by Chemotherapy and Rituximab.

Blood ◽

10.1182/blood.v106.11.159.159 ◽

2005 ◽

Vol 106 (11) ◽

pp. 159-159

Author(s):

Karen Leroy ◽

Jean-Philippe Jais ◽

Corinne Haioun ◽

David Rickman ◽

Aurelien de Reynies ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Treatment Regimen ◽

Clinical Characteristics ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Molecular profiles have been shown to correlate with survival in patients with diffuse large B-cell lymphoma (DLBCL) receiving conventional chemotherapy. However, most patients now receive monoclonal anti-CD20 antibodies in addition to chemotherapy, which might erase the poor prognosis associated with some markers (Mounier et al, Blood2003;101:4279) and reveal new prognostic factors related to rituximab mechanisms of action. This prompted us to undertake a gene expression study on the samples of patients (pts) included in the GELA LNH98-5 study that compared CHOP and rituximab-CHOP (R-CHOP) regimen. We collected all available frozen tissue samples from patients included into the LNH98-5 trial and completed the series with patients treated with the same regimens in participating centers during the same period. All those patients were between 60 and 80 years old, had histologically reviewed DLBCL, Ann Arbor stage II to IV disease and an ECOG Performance Status ≤3. High quality RNA from 53 patient (43 from the study itself and 10 from the additional cohort) treated with CHOP (30 pts) or R-CHOP (23 pts) were analyzed with Affymetrix HU133A micro-arrays. The main clinical characteristics of this subset of patients were similar to that of the remaining group of 346 patients involved in the LNH98-5 study. Two parameters were strongly correlated with disease progression: a high International Prognostic Index (IPI = 4 or 5) (relative risk (RR) 3.9 when compared to pts with an IPI = 2 or 3, p=0.002) and treatment regimen (CHOP: RR 4.2 when compared to R-CHOP, p=0.001). In both treatment arms, patients with a germinal center (GC) DLBCL profile had a better outcome than patients with an activated B-cell (ABC) one (ABC versus GC, RR of progression 2.6, p=0.06) and several transcripts previously associated with prognosis, such as BCL6, showed a strong correlation with survival (BCL6 low versus BCL6 high, RR of progression 3.1, p=0.004), further corroborating the clinical relevance of this series of patients. We then used Cox models adjusted for IPI and treatment regimen to test the association with outcome of each Affymetrix microarray probeset 1) in the entire population, 2) or with a differential effect according to the treatment regimen.This strategy allowed us to identify several transcripts that were highly correlated with survival, either in both groups or specifically in the R-CHOP group. Interestingly, some of these transcripts are related to apoptosis regulation, immune cell infiltration or B-cell signal transduction. We are currently investigating the prognostic significance of this series of transcripts, using Quantitative RT-PCR, in an independent set of 43 DLBCL patients who presented the same clinical characteristics than the initial test group and received R-CHOP in GELA centers after the closure of the LNH98-5 trial.

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Follicular lymphoma grade 3B and diffuse large B-cell lymphoma present a histopathological and molecular continuum lacking features of progression/transformation

Haematologica ◽

10.3324/haematol.2021.279351 ◽

2022 ◽

Author(s):

Karoline Koch ◽

Julia Richter ◽

Christoph Hanel ◽

Andreas Huttmann ◽

Ulrich Duhrsen ◽

...

Keyword(s):

Gene Expression ◽

Follicular Lymphoma ◽

B Cell ◽

Growth Pattern ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

The sole distinguishing feature of follicular lymphoma grade 3B and diffuse large B-cell lymphoma is the growth pattern assessed by histopathology analysis. Diffuse growth defines diffuse large B-cell lymphoma but the clinical relevance of this finding when occurring in follicular lymphoma grade 3B is uncertain. To address this question, individual and coexisting follicular lymphoma grade 3B and diffuse large B-cell lymphoma were separated and analyzed for immunophenotype and molecular genetic features by fluorescence in situ hybridization, targeted sequencing and gene expression profiling. Clinical features of follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma were studied in homogeneously treated patients from a prospective randomized trial. Follicular lymphoma grade 3B and diffuse large B-cell lymphoma frequently show intermediate growth pattern and/or occurred simultaneously in the same tissue at the time of initial diagnosis. When occurring simultaneously follicular lymphoma grade 3B and diffuse large B-cell lymphoma do not differ significantly in genetic aberrations or phenotype but distinct features in gene expression reflect divergent microenvironment. Follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma do not differ in major clinical parameters such as international prognostic index, response to immunochemotherapy, progression or overall survival. Follicular lymphoma grade 3B and simultaneous diffuse large B-cell lymphoma are molecularly homogenous. Histological detection of diffuse large B-cell lymphoma is not associated with features of a more aggressive disease and does not reflect transformation or progression of follicular lymphoma Grade 3B.

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Prognostic significance of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), and vascularity in diffuse large B-cell lymphoma treated with immunochemotherapy (R-CHOP)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8581 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8581-8581

Author(s):

D. Gratzinger ◽

R. Advani ◽

S. Zhao ◽

N. Talreja ◽

R. J. Tibshirani ◽

...

Keyword(s):

B Cell ◽

Cox Regression ◽

De Novo ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Significance ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

8581 Background: Diffuse large B cell lymphoma (DLBCL) cells coexpress VEGF, VEGFR1 and VEGFR2. In patients (pts) treated with CHOP chemotherapy alone, VEGFR1 predicted improved overall survival (OS) while microvessel density (MVD) predicted poorer OS; VEGF and VEGFR2 were not predictive (Lab Invest. 2008;88:38). We now assess these factors in pts treated with R-CHOP. Methods: 162 pts with de novo DLBCL treated with R-CHOP and median followup of 44 months were evaluated retrospectively with immunohistochemistry on tissue microarrays. Scoring: VEGF, VEGFR1, VEGFR2, and phosphoVEGFR2 (pVEGFR2) in lymphoma cells (categorical variable) <5%, none; 5–30%, weak; >30%, strong. MVD (continuous variable): average CD34+ microvessels/4 hpf. Statistics: univariate Cox proportional hazards regression, and multivariate Cox regression for testing independence from the International Prognostic Index (IPI) for two endpoints, OS and progression-free survival (PFS). Pearson chi-square testing for independence of variables. Results: VEGF and MVD did not correlate with OS or PFS. Pts with higher VEGFR2 (53%) had poorer OS but not PFS independent of the IPI (z=3.15, p=0.0016; 2 yr OS 100%/84%/76%). Pts with any pVEGFR2 (13%) had worse PFS independent of IPI (z=1.98, p=0.048) and a trend toward poor OS (p=0.056). VEGFR1 did not correlate with OS or PFS in the group as a whole. Since VEGFR1 and VEGFR2 expression correlate strongly (Χ2=56, p =9.8E-12) opposing associations with outcome could be masked. On subset analysis the 39% of pts with weak VEGFR2 had better OS with higher VEGFR1 (z=-1.64, p=0.016; 2 yr OS 68%/85%/92%). Conclusions: In contrast to our prior observations in CHOP treated pts, in DLBCL treated with R-CHOP MVD was not prognostically significant. The association of VEGFR1 with better OS was previously seen with CHOP alone, whereas the correlation of VEGFR2 and phosphorylated VEGFR2 with poorer OS was only seen with R-CHOP. Independent confirmation will be important, especially because multiple comparisons were made with 5 predictors and 2 endpoints tested. It is possible that VEGFR1 and VEGFR2 oppose each other functionally; future studies are indicated to address the mechanism of this effect. No significant financial relationships to disclose.

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Prognostic factors in patients with diffuse large B-cell lymphoma

Medicinski pregled ◽

10.2298/mpns0904171u ◽

2009 ◽

Vol 62 (3-4) ◽

pp. 171-176

Author(s):

Vera Uzurov-Dinic ◽

Aleksandar Savic ◽

Tanja Lazarevic ◽

Vesna Cemerikic-Martinovic ◽

Danijela Agic ◽

...

Keyword(s):

Complete Remission ◽

B Cell ◽

Cell Lymphoma ◽

Remission Rate ◽

International Prognostic Index ◽

Prognostic Significance ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Diffuse large B-cell lymphoma is an aggressive type of lymphoma, potentially curable, with heterogeneous prognosis. The aim of this study was to determine prognostic significance of clinical, laboratory and immunohystochemical factors. The retrospective study was done in 50 patients with diffuse large B-cell lymphoma. The following parameters were investigated: demographic (age, sex), clinical (time to diagnosis, B symptoms, clinical stage), laboratory (erythrocyte sedimentation rate, haemoglobin, lactate dehydrogenase, albumine), standard and revised international prognostic index, and immunohystochemical parameters, cluster designation 20, B-cell-2, and Ki67 expression. There were 20 females and 30 males, their average age being 54 (22-83) years. The majority of patients had advanced disease: B symptoms in 76%, III and IV stage in 78%, increased lactate dehydrogenase in 74%, high risk standard international prognostic index in 62% of patients. B-cell leukemia/lymphoma 2 expression was found in 57%, and high Ki67 in 62% of patients.Rituximab-Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone and Rituximab-Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Etoposide, Prednisolone were conducted in 72% (36), and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone and Cyclophosphamide, Hydroxydaunorubicin, Vincristine, Prednisolone-like treatment in 28% (14) of patients. The complete remission rate was 74%, and the partial remission rate was 9%. A significant difference in survival was found between low intermediate and high intermediate S-IPI risk groups, good and bad risk R-IPI, and patients with complete remission and patients with other treatment responses. The other parameters, including Bcl-2 and Ki67 expression, and type of treatment did not show significant influence on survival. The expected five-year survival was 69 %. Our results have shown that international prognostic index, and complete remission status have prognostic significance in diffuse large B-cell lymphomas.

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Frequency and Clinical Association of NY-ESO-1 Gene Expression in Diffuse Large B-cell Lymphoma.

10.21203/rs.3.rs-19722/v1 ◽

2020 ◽

Author(s):

Irma Olarte Carrilo ◽

Christian Ramos Peñafiel ◽

Enrique Miranda Peralta ◽

Efrain Garrido Guerrero ◽

JUAN COLAZO JALOMA ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Clinical Parameters ◽

Expression Levels ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background Diffuse Large B-cell Lymphoma, a heterogeneous disease, is influenced by complex network of gene interactions. In current study, we aimed to evaluate the frequency of expression and determine the expression levels of the NY-ESO-1 gene in patients with DLBCL, as well as to examine its relationship with clinical parameters and survival. Methods We analyzed NY-ESO-1 gene expression levels using real-time quantitative RT-PCR (qRT-PCR) in 112 patients with DLBCL. The associations between the expression of the NY-ESO-1 gene and the clinical variables were evaluated using the chi-square test and Fisher’s exact test. Overall survival (OS) was determined using the Kaplan-Meier method. Result The results showed that the NY-ESO-1 gene was expressed in 46.4% (52/112) of patients with DLBCL, and NY-ESO-1 gene expression was associated with clinical parameters such as LDH, clinical stage, international prognostic index (IPI) (p≤0.05). High levels of NY-ESO-1 gene expression were correlated with advanced disease stages, and the survival rates after 5.3 years of tracking were lower in the patients expressing the NY-ESO-1 gene (66.4%) than in those not expressing the gene (23.1%). Conclusion In conclusion, the expression levels of the NY-ESO-1 gene in patients with DLBCL may be of great utility for diagnosing and determining the prognosis of this disease.

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