scholarly journals Integrated bioinformatics analysis reveals dynamic candidate genes and signaling pathways involved in the progression and prognosis of diffuse large B-cell lymphoma

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12394
Author(s):  
Alice Charwudzi ◽  
Ye Meng ◽  
Linhui Hu ◽  
Chen Ding ◽  
Lianfang Pu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Cells ◽  
Bioinformatics Analysis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hub Genes ◽  
The Core ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Core Genes

Background Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignancy with varied outcomes. However, the fundamental mechanisms remain to be fully defined. Aim We aimed to identify core differentially co-expressed hub genes and perturbed pathways relevant to the pathogenesis and prognosis of DLBCL. Methods We retrieved the raw gene expression profile and clinical information of GSE12453 from the Gene Expression Omnibus (GEO) database. We used integrated bioinformatics analysis to identify differentially co-expressed genes. The CIBERSORT analysis was also applied to predict tumor-infiltrating immune cells (TIICs) in the GSE12453 dataset. We performed survival and ssGSEA (single-sample Gene Set Enrichment Analysis) (for TIICs) analyses and validated the hub genes using GEPIA2 and an independent GSE31312 dataset. Results We identified 46 differentially co-expressed hub genes in the GSE12453 dataset. Gene expression levels and survival analysis found 15 differentially co-expressed core hub genes. The core genes prognostic values and expression levels were further validated in the GEPIA2 database and GSE31312 dataset to be reliable (p < 0.01). The core genes’ main KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichments were Ribosome and Coronavirus disease-COVID-19. High expressions of the 15 core hub genes had prognostic value in DLBCL. The core genes showed significant predictive accuracy in distinguishing DLBCL cases from non-tumor controls, with the area under the curve (AUC) ranging from 0.992 to 1.00. Finally, CIBERSORT analysis on GSE12453 revealed immune cells, including activated memory CD4+ T cells and M0, M1, and M2-macrophages as the infiltrates in the DLBCL microenvironment. Conclusion Our study found differentially co-expressed core hub genes and relevant pathways involved in ribosome and COVID-19 disease that may be potential targets for prognosis and novel therapeutic intervention in DLBCL.

Gene Expression Signature of Host Immune Response Is Predictive of Follicular Lymphoma Patient Survival in Independent Cohorts, and Correlates with Transformation to Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2951-2951
Author(s):  
Ash A Alizadeh ◽  
Andrew J Gentles ◽  
Sylvia K Plevritis ◽  
Ronald Levy
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Immune Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Independent Cohort

Abstract Abstract 2951 Poster Board II-927 Background: Expression signatures of infiltrating immune cells [1] have been shown to predict survival in follicular lymphoma (FL), but have not been cross-validated in independent patient cohorts [2,3]. These signatures may relate biologically to the frequency of infiltrating including T-cells and macrophages, or to specific transcription programs within tumor cells and/or the tumor microenvironment. We sought to evaluate the validity of this model in an independent cohort of patients with FL, assessing its relationship to outcomes including histological transformation and death. Methods: The immune response (IR) predictor score proposed by Dave et al. [1] was applied to gene expression data from an independent cohort of 88 FL patients [4] with known survival outcomes and history of transformation to diffuse large B-cell lymphoma (DLBCL). Genes (n=66) corresponding to IR1 and IR2 signatures were mapped from Affymetrix microarrays [1] to a custom cDNA array [4] via Entrez Gene ID, and the composite IR score was calculated per the scheme proposed by Dave et al. Results: The IR score was predictive of patient outcome in the 88 patient test set as a continuous variable (p=0.001, HR=2.01, 95% CI 0.50-1.30). Partitioning of patients into high and low risk groups based on the median IR score across the cohort robustly separated survival curves (Figure A). The IR score was significantly higher in FL patients known to undergo transformation to DLBCL (Figure B: mean IR score of -0.6 in non-transforming FL vs. -0.2 in transforming FL; p∼10-11, t-test). Conclusions: The IR score of Dave et al. was highly significant as a predictor of survival in the independent patient cohort [4]. Moreover, the score was significantly associated with propensity of FL to transform to DLBCL. To our knowledge, immune cell infiltration has not previously been implicated in transformation. 1. Dave SS et al. (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21): 2159-2169. 2. Tibshirani R (2005) Immune signatures in follicular lymphoma. N Engl J Med 352: 1496-1497. 3. Chu G Hong WJ, Warnke R, Chu G (2005). Immune Signatures in Follicular Lymphoma (Corres). N Engl J Med. 352: 1496-1497. 4. Glas AM et al. (2005) Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. Blood 105(1): 301-307. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Identification of hub genes associated with the pathogenesis of diffuse large B-cell lymphoma subtype one characterized by host response via integrated bioinformatic analyses

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10269
Author(s):  
Lingna Zhou ◽  
Liya Ding ◽  
Yuqi Gong ◽  
Jing Zhao ◽  
Gong Xin ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Host Response ◽  
Cell Lymphoma ◽  
Enrichment Analysis ◽  
B Cell Lymphoma ◽  
Hub Genes ◽  
Hub Gene ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Background Host response diffuse large B-cell lymphoma (HR DLBCL) shares features of histologically defined T-cell/histiocyte-rich B-cell lymphoma, including fewer genetic abnormalities, frequent splenic and bone marrow involvement, and younger age at presentation. HR DLBCL is inherently less responsive to the standard treatment for DLBCL. Moreover, the mechanism of infiltration of HR DLBCL with preexisting abundant T-cells and dendritic cells is unknown, and their associated underlying immune responses incompletely defined. Here, hub genes and pathogenesis associated with HR DLBCL were explored to reveal molecular mechanisms and treatment targets. Methods Differentially expressed genes were identified in three datasets (GSE25638, GSE44337, GSE56315). The expression profile of the genes in the GSE53786 dataset was used to constructed a co-expression network. Protein-protein interactions analysis in the modules of interest identified candidate hub genes. Then screening of real hub genes was carried out by survival analysis within the GSE53786 and GSE10846 datasets. Expression of hub genes was validated in the Gene expression profiling interactive analysis, Oncomine databases and human tissue specimens. Functional enrichment analysis and Gene set enrichment analysis were utilized to investigate the potential mechanisms. Tumor Immune Estimation Resource and The Cancer Genome Atlas were used to mine the association of the hub gene with tumor immunity, potential upstream regulators were predicted using bioinformatics tools. Results A total of 274 common differentially expressed genes were identified. Within the key module, we identified CXCL10 as a real hub gene. The validation of upregulated expression level of CXCL10 was consistent with our study. CXCL10 might have a regulatory effect on tumor immunity. The predicted miRNA (hsa-mir-6849-3p) and transcription factor (IRF9) might regulate gene expression in the hub module.

Impact of Tumor Infiltrating T Cells in Patients with Diffuse Large B-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1572-1572
Author(s):  
Shahryar Kiaii ◽  
Andrew James Clear ◽  
John G Gribben
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
B Cell ◽  
Immune Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Treated Group ◽  
Prognostic Impact ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 1572 Previous studies have demonstrated the importance of the non-malignant tumor-infiltrating immune cells in the tumor microenvironment at diagnosis in patients with non-Hodgkin's lymphoma (NHL). We aimed to investigate the molecular mechanisms whereby tumor infiltrating T cells (TILs) are altered in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). We used gene expression profiling of highly purified CD4 and CD8 infiltrating T-cells (TILs) from FL patients and reported that PMCH, ETV1 and NAMPT are highly expressed in both CD4 and CD8 TILs and showed in tissue microarrays (TMA) that expression of pro-melanin-concentrating hormone (PMCH), ets variant 1 (ETV1) and nicotinamide phosphoribosyltransferase (NAMPT) in T-cells have prognostic impact in disease specific survivals (DSS) and time to transformation (TT) in patients with FL. In addition, PMCH and NAMPT were shown to be independently significant in TT in multivariate analysis. We next examined expression of these gene products in T cells in FL samples before and after transformation to DLBCL (n=29). Comparing total number of positive cells for expression of proteins of interest, we demonstrate there is a significant decline in PMCH (p=0.035), EVT1 (p=0.018) and NAMPT (p=0.0136) expressing cells after transformation. We further investigated the prognostic impact of expression of these proteins in T cells in patients with DLBCL in two treatment groups, those receiving rituximab (n=68) and in a historic non-rituximab (n=130) treated cohort. By assessing the number of positive cells and the impact on survival using Kaplan-Meier analysis, we now show that the T-cell expressed genes PMCH, ETV1 and NAMPT have prognostic significance for overall survival (OS) in patients with DLBCL. Patients with higher number of PMCH expressing T-cells showed significant longer survivals in both rituximab (p=0.027) and non-rituximab (p=0.033) treated groups. In contrast to PMCH, and in line with our previous data in FL, patients with higher number of NAMPT expressing cells showed significantly shorter OS in the rituximab (p=0.046) treated group, with a trend towards shorter OS in non-rituximab (p=0.064) treated group. Patients with higher percentage of ETV1 expressing cells had longer OS in the non-Rituximab group (p=0.008), with only a trend towards OS with rituximab treatment (p=0.067). We are examining this further in a larger cohort of rituximab treated patients. Our previous data has indicated that TILs in patients with FL are abnormal in terms of their gene expression and function. We now show that changes in protein expression in TILs have an impact on transformation in patients with FL and on survival in both FL and DLBCL. We are further characterizing the mechanisms of gene expression alteration in TILs of patients with FL and DLBCL and its functional consequences in the biology and of the disease. It appears that altered gene expression in TILs plays a fundamental role in transformation and may be important in the survivals and biology of NHL. Since non-malignant infiltrating immune cells have a crucial role in the outcome of patients with FL and DLBCL, understanding the nature and impact of the abnormalities induced in TILs in these patients is crucial before any immunotherapeutic strategies can be implemented to attempt to alter the immune microenvironment in NHL. Disclosures: Gribben: Celgene: Honoraria.

scholarly journals NCAPD3 Regulates Tumor Growth and Predicts Prognosis in Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5045-5045
Author(s):  
Juan Yang ◽  
Ying Li ◽  
Ya Zhang ◽  
Xiangxiang Zhou ◽  
Yi Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Bioinformatics Analysis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Control Group ◽  
Large B Cell Lymphoma ◽  
Reactive Hyperplasia ◽  
Large B Cell

Introduction NCAPD3 (Non-SMC Condensin II Complex Subunit D3) is a regulatory subunit of the condensing-2 complex. Recent studies have shown that somatic mutations in genes encoding subunits of condensins associated with microcephaly, primary autosomal recessive and several cancers. NCAPD3 was highlighted as an outcome predictor in pancreatic ductal adenocarcinoma (PDAC) and a new biomarker for subtype-1 prostate cancer that improves prognostication. Yet, no literature has been reported regarding the expression and biological role of NCAPD3 in diffuse large B cell lymphoma (DLBCL). Hence, the aim of our study is to evaluate the functional significance and mechanism of NCAPD3 in DLBCL. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers with informed consents. Expression levels of NCAPD3 mRNA and protein in DLBCL cell lines and PBMCs were detected by quantitative RT-PCR and western blotting. Immunohistochemistry (IHC) was conducted to assess the expression of NCAPD3 on paraffin-embedded tissues from 70 de novo DLBCL patients (study group) and 35 reactive hyperplasia patients (control group) with informed contents. Microarray datasets GSE32918 and GSE83632 were obtained from Gene Expression Omnibus. Survival analysis, protein-protein interaction (PPI) and gene set enrichment analysis (GSEA) in gene expression profiles were performed. Lentivirus vectors either targeting NCAPD3 (shNCAPD3) or empty lentiviral vector (shControl) were stably transfected into DLBCL cells. Cell proliferation was analyzed by cell counting kit (CCK-8). The apoptosis and cell cycle assays were carried out by flow cytometry. p < 0.05 was considered statistically significant. Results Markedly increased expression of NCAPD3 was detected in DLBCL cell lines at mRNA and protein level compared to those in healthy volunteers' PBMCs (Fig. 1a-b). We also observed higher NCAPD3 expression levels in DLBCL tissues than in reactive hyperplasia upon IHC staining (Fig. 1c). Expression of NCAPD3 protein was revealed in significant positive correlation with advanced Ann Arbor stage (p=0.046) and IPI score (p=0.017, Fig. 1d). Bioinformatics analysis showed that high NCAPD3 expression in DLBCL was turned up to be correlate with shorter overall survival according to GSE32918 (p=0.013, Fig. 2a). PPI network and GSEA indicated that NCAPD3 was functional enriched in chromatin regulation, cell cycle, histone methylation, NF-κB signaling and Toll-like receptor signaling pathway (Fig. 2b-c). Relevant mechanism is now the focus of ongoing experiments. Lentivirus mediated loss-of-function assays were performed to further investigate the biological role of NCAPD3 in DLBCL. Effective knockdown (shNCAPD3) was confirmed by qRT-PCR and western blot (Fig. 3a-b). Stable expression of shNCAPD3 in DLBCL cells exhibited growth suppression, increased fast-onset apoptosis, and induced GO/G1 phase arrest when compared to the control group (Fig. 3c-e). Conclusion Our investigations identified for the first time the oncogenic role of NCAPD3 in DLBCL tumorigenesis by bioinformatics analysis and in vitro evaluation. Expression of NCAPD3 was upregulated, and associated with adverse outcome of DLBCL patients. NCAPD3 inhibition by RNAi exerted anti-tumor efficacy in inhibiting cell growth, promoting apoptosis and blocking cell cycle. This study suggests that Sirt6 could be a potential molecular target for the treatment of DLBCL. Further study on it is under way. Disclosures No relevant conflicts of interest to declare.

scholarly journals Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Selin Merdan ◽  
Kritika Subramanian ◽  
Turgay Ayer ◽  
Johan Van Weyenbergh ◽  
Andres Chang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
B Cell ◽  
Risk Prediction ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Signatures ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractThe clinical risk stratification of diffuse large B-cell lymphoma (DLBCL) relies on the International Prognostic Index (IPI) for the identification of high-risk disease. Recent studies suggest that the immune microenvironment plays a role in treatment response prediction and survival in DLBCL. This study developed a risk prediction model and evaluated the model’s biological implications in association with the estimated profiles of immune infiltration. Gene-expression profiling of 718 patients with DLBCL was done, for which RNA sequencing data and clinical covariates were obtained from Reddy et al. (2017). Using unsupervised and supervised machine learning methods to identify survival-associated gene signatures, a multivariable model of survival was constructed. Tumor-infiltrating immune cell compositions were enumerated using CIBERSORT deconvolution analysis. A four gene-signature-based score was developed that separated patients into high- and low-risk groups. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The gene signatures were successfully validated with the deconvolution output. Correlating the deconvolution findings with the gene signatures and risk score, CD8+ T-cells and naïve CD4+ T-cells were associated with favorable prognosis. By analyzing the gene-expression data with a systematic approach, a risk prediction model that outperforms the existing risk assessment methods was developed and validated.

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