Identification of a prognostic metabolic gene signature in diffuse large B-cell lymphoma.
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ABSTRACT:
SUBMITTER: Wang H
PROVIDER: S-EPMC8278125 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although immunotherapy is a potential strategy to resist cancers, due to the inadequate acknowledge, this treatment is not always effective for diffuse large B cell lymphoma (DLBCL) patients. Based on the current situation, it is critical to systematically investigate the immune pattern. According to the result of univariate and multivariate cox proportional hazards, LASSO regression and Kaplan-Meier survival analysis on immune-related genes (IRGs), a prognostic signature, containing 14 IRGs (AQP9, LMBR1L, FGF20, TANK, CRP, ORM1, JAK1, BACH2, MTCP1, IFITM1, TNFSF10, FGF12, RFX5, and LAP3), was built. This model was validated by external data, and performed well. DLBCL patients were divided into low- and high-risk groups, according to risk scores from risk formula. The results of CIBERSORT showed that different immune status and infiltration pattern were observed in these two groups. Gene set enrichment analysis (GSEA) indicated 12 signaling pathways were significantly enriched in the high-risk group, such as natural killer cell-mediated cytotoxicity, toll-like receptor signaling pathway, and so on. In summary, 14 clinically significant IRGs were screened to build a risk score formula. This formula was an accurate tool to provide a certain basis for the treatment of DLBCL patients.
| S-EPMC7902938 | biostudies-literature
Project description:RNA binding proteins (RBPs) are increasingly appreciated as being essential for normal hematopoiesis and have a critical role in the progression of hematological malignancies. However, their functional consequences and clinical significance in diffuse large B-cell lymphoma (DLBCL) remain unknown. Here, we conducted a systematic analysis to identify RBP-related genes affecting DLBCL prognosis based on the Gene Expression Omnibus database. By univariate and multivariate Cox proportional hazards regression (CPHR) methods, six RBPs-related genes (CMSS1, MAEL, THOC5, PSIP1, SNIP1, and ZCCHC7) were identified closely related to the overall survival (OS) of DLBCL patients. The RBPs signature could efficiently distinguished low-risk from high-risk patients and could serve as an independent and reliable factor for predicting OS. Moreover, Gene Set Enrichment Analysis revealed 17 significantly enriched pathways between high- versus low-risk group, including the regulation of autophagy, chronic myeloid leukemia, NOTCH signaling pathway, and B cell receptor signaling pathway. Then we developed an RBP-based nomogram combining other clinical risk factors. The receiver operating characteristic curve analysis demonstrated high prognostic predictive efficiency of this model with the area under the curve values were 0.820 and 0.780, respectively, in the primary set and entire set. In summary, our RBP-based model could be a novel prognostic predictor and had the potential for developing treatment targets for DLBCL.
| S-EPMC8026940 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL) is an extremely heterogeneous tumor entity, which makes prognostic prediction challenging. The tumor microenvironment (TME) has a crucial role in fostering and restraining tumor development. Consequently, we performed a systematic investigation of the TME and genetic factors associated with DLBCL to identify prognostic biomarkers for DLBCL. Data for a total of 1,084 DLBCL patients from the Gene Expression Omnibus database were included in this study, and patients were divided into a training group, an internal validation group, and two external validation groups. We calculated the abundance of immune-stromal components of DLBCL and found that they were related to tumor prognosis and progression. Then, differentially expressed genes were obtained based on immune and stromal scores, and prognostic TME-related genes were further identified using a protein-protein interaction network and univariate Cox regression analysis. These genes were analyzed by the least absolute shrinkage and selection operator Cox regression model to establish a seven-gene signature, comprising TIMP2, QKI, LCP2, LAMP2, ITGAM, CSF3R, and AAK1. The signature was shown to have critical prognostic value in the training and validation sets and was also confirmed to be an independent prognostic factor. Subgroup analysis also indicated the robust prognostic ability of the signature. A nomogram integrating the seven-gene signature and components of the International Prognostic Index was shown to have value for prognostic prediction. Gene set enrichment analysis between risk groups demonstrated that immune-related pathways were enriched in the low-risk group. In conclusion, a novel and reliable TME relevant gene signature was proposed and shown to be capable of predicting the survival of DLBCL patients at high risk of poor survival.
| S-EPMC7938316 | biostudies-literature
Project description:Background: The diffuse large B-cell lymphoma (DLBCL) is a heterogeneous lymphoma with a dismal outcome, due to approximately 40% patients will be relapsed or refractory to the standard therapy of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Therefore, we need urgently to explore the approach to classify the risk of DLBCL patients accurately and accurately targeting therapy. The ribosome is a vital cellular organelle that is mainly responsible for translation mRNA into protein, moreover, more and more reports revealed that ribosome was associated with cellular proliferation and tumorigenesis. Therefore, our study aimed to construct a prognostic model of DLBCL patients using ribosome-related genes (RibGs). Method: We screened differentially expressed RibGs between healthy donors' B cells and DLBCL patients' malignant B cells in GSE56315 dataset. Next, we performed analyses of univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses to establish the prognostic model consisting of 15 RibGs in GSE10846 training set. Then, we validated the model by a range of analyses including Cox regression, Kaplan-Meier survival, ROC curve, and nomogram in training and validation cohorts. Results: The RibGs model showed a reliably predictive capability. We found the upregulated pathways in high-risk group most associated with innate immune reaction such as interferon response, complement and inflammatory responses. In addition, a nomogram including age, gender, IPI score and risk score was constructed to help explain the prognostic model. We also discovered the high-risk patients were more sensitive to some certain drugs. Finally, knocking out the NLE1 could inhibit the proliferation of DLBCL cell lines. Conclusion: As far as we know, it is the first time to predict the prognosis of DLBCL using the RibGs and give a new sight for DLBCL treatment. Importantly, the RibGs model could be acted as a supplementary to the IPI in classifying the risk of DLBCL patients.
| S-EPMC9969582 | biostudies-literature
Project description:BackgroundDiffuse large B cell lymphoma (DLBCL) is the most common lymphoma in adults. Metabolic reprogramming in tumors is closely related to the immune microenvironment. This study aimed to explore the interactions between metabolism-associated genes (MAGs) and DLBCL prognosis and their potential associations with the immune microenvironment.MethodsGene expression and clinical data on DLBCL patients were obtained from the GEO database. Metabolism-associated molecular subtypes were identified by consensus clustering. A prognostic risk model containing 14 MAGs was established using Lasso-Cox regression in the GEO training cohort. It was then validated in the GEO internal testing cohort and TCGA external validation cohort. GO, KEGG and GSVA were used to explore the differences in enriched pathways between high- and low-risk groups. ESTIMATE, CIBERSORT, and ssGSEA analyses were used to assess the immune microenvironment. Finally, WGCNA analysis was used to identify two hub genes among the 14 model MAGs, and they were preliminarily verified in our tissue microarray (TMA) using multiple fluorescence immunohistochemistry (mIHC).ResultsConsensus clustering divided DLBCL patients into two metabolic subtypes with significant differences in prognosis and the immune microenvironment. Poor prognosis was associated with an immunosuppressive microenvironment. A prognostic risk model was constructed based on 14 MAGs and it was used to classify the patients into two risk groups; the high-risk group had poorer prognosis and an immunosuppressive microenvironment characterized by low immune score, low immune status, high abundance of immunosuppressive cells, and high expression of immune checkpoints. Cox regression, ROC curve analysis, and a nomogram indicated that the risk model was an independent prognostic factor and had a better prognostic value than the International Prognostic Index (IPI) score. The risk model underwent multiple validations and the verification of the two hub genes in TMA indicated consistent results with the bioinformatics analyses.ConclusionsThe molecular subtypes and a risk model based on MAGs proposed in our study are both promising prognostic classifications in DLBCL, which may provide novel insights for developing accurate targeted cancer therapies.
| S-EPMC9036805 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL) presents a great clinical challenge and has a poor prognosis, with immune-related genes playing a crucial role. We aimed to develop an immune-related prognostic signature for improving prognosis prediction in DLBCL. Samples from the GSE31312 dataset were randomly allocated to discovery and internal validation cohorts. Univariate Cox, random forest, LASSO regression and multivariate Cox analyses were utilized to develop a prognostic signature, which was verified in the internal validation cohort, entire validation cohort and external validation cohort (GSE10846). The tumor microenvironment was investigated using the CIBERSORT and ESTIMATE tools. Gene set enrichment analysis (GSEA) was further applied to analyze the entire GSE31312 cohort. We identified four immune-related genes (CD48, IL1RL, PSDM3, RXFP3) significantly associated with overall survival. Based on discovery and validation cohort analyses, this four-gene signature could classify patients into high- and low-risk groups, with significantly different prognoses. Activated memory CD4 T cells and activated dendritic cells were significantly decreased in the high-risk group, and these patients had lower immune scores. GSEA revealed enrichment of signaling pathways, such as T cell receptor, antigen receptor-mediated, antigen processing and presentation of peptide antigen via MHC class I, in the low-risk group. In conclusion, a robust signature based on four immune-related genes was successfully constructed for predicting prognosis in DLBCL patients.
| S-EPMC8544299 | biostudies-literature
Project description:BackgroundImmune cells in the tumor microenvironment are an important prognostic indicator in diffuse large B-cell lymphoma (DLBCL). However, information on the heterogeneity and risk stratification of these cells is limited. We sought to develop a novel immune model to evaluate the prognostic intra-tumoral immune landscape of patients with DLBCL.MethodsThe ESTIMATE and CIBERSORT algorithms were used to estimate the numbers of 22 infiltrating immune cells based on the gene expression profiles of 229 patients with DLBCL who were recruited from a public database. The least absolute shrinkage and selection operator (Lasso) penalized regression analyses and nomogram model were used to construct and evaluate the prognostic immunoscore (PIS) model for overall survival prediction. An immune gene prognostic score (IGPS) was generated by Gene Set Enrichment Analysis (GSEA) and Cox regression analysis was and validated in an independent NCBI GEO dataset (GSE10846).ResultsA higher proportion of activated natural killer cells was associated with a poor outcome. A total of five immune cells were selected in the Lasso model and DLBCL patients with high PIS showed a poor prognosis (hazard ratio (HR) 2.16; 95% CI [1.33-3.50]; P = 0.002). Differences in immunoscores and their related outcomes were attributed to eight specific immune genes involved in the cytokine-cytokine receptor interaction and chemokine signaling pathways. The IGPS based on a weighted formula of eight genes is an independent prognostic factor (HR: 2.14, 95% CI [1.40-3.28]), with high specificity and sensitivity in the validation dataset.ConclusionsOur findings showed that a PIS model based on immune cells is associated with the prognosis of DLBCL. We developed a novel immune-related gene-signature model associated with the PIS model and enhanced the prognostic functionality for the prediction of overall survival in patients with DLBCL.
| S-EPMC7414766 | biostudies-literature
Project description:Alongside various clinical prognostic factors for diffuse large B-cell lymphoma (DLBCL) such as the international prognostic index (IPI) components (ie, age, tumor stage, performance status, serum lactate dehydrogenase concentration, and number of extranodal sites), prognostic gene signatures have recently shown promising efficacy. However, previously developed signatures for DLBCL suffer from many major inadequacies such as lack of reproducibility in external datasets, high number of members (genes) in a signature, and inconsistent association with the survival time in various datasets. Accordingly, we sought to find a reproducible prognostic gene signature with a minimal number of genes. Seven datasets-namely GSE10856 (420 samples), GSE31312 (470 samples), GSE69051 (157 samples), GSE32918 (172 samples), GSE4475 (123 samples), GSE11318 (203 samples), and GSE34171 (91 samples)-were employed. The datasets were randomly categorized into training (1219 samples comprising GSE10856, GSE31312, GSE69051, and GSE32918) and validation (417 samples consisting of GSE4475, GSE11318, and GSE34171) groups. Through the univariate Cox proportional hazards analysis, common genes associated with the overall survival time with a P value less than 0.001 and a false discovery rate less than 5% were identified in 1219 patients included in the 4 training datasets. Thereafter, the common genes were entered into a multivariate Cox proportional hazards analysis encompassing the common genes and the international prognostic index (IPI) factors as covariates, and then only common genes with a significant level of difference (P?<?0.01 and z-score >2 or <-2) were selected to reconstruct the prognostic signature. After the analyses, a 7-gene prognostic signature was developed, which efficiently predicted the survival time in the training dataset (Ps?<?0.0001). Subsequently, this signature was tested in 3 validation datasets. Our signature was able to strongly predict clinical outcomes in the validation datasets (Ps?<?0.0001). In the multivariate Cox analysis, our outcome predictor was independent of the routine IPI components in both training datasets (Ps?<?0.0001). Furthermore, our outcome predictor was the most powerful independent prognostic variable (Ps?<?0.0001). We developed a potential reproducible prognostic gene signature which was able to robustly discriminate low-risk patients with DLBCL from high-risk ones.
| S-EPMC6704056 | biostudies-literature
Project description:BackgroundS100A8, a calcium-binding protein belonging to the S100 family, is involved in immune responses and multiple tumor pathogens. Diffuse large B-cell lymphoma (DLBCL) is one of the most common types of B-cell lymphoma and remains incurable in 40% of patients. However, the role of S100A8 and its regulation of the immune response in DLBCL remain unclear.MethodsThe differential expression of S100A8 was identified via the GEO and TCGA databases. The prognostic role of S100A8 in DLBCL was calculated using the Kaplan-Meier curve. The function enrichment of differentially expressed genes (DEGs) was explored through GO, KEGG, GSEA, and PPI analysis. In our cohort, the expression of S100A8 was verified. Meanwhile, the biological function of S100A8 was applied after the inhibition of S100A8 in an in vitro experiment. The association between S100A8 and immune cell infiltration and treatment response in DLBCL was analyzed.ResultsS100A8 was significantly overexpressed and related to a poor prognosis in DLBCL patients. Function enrichment analysis revealed that DEGs were mainly enriched in the IL-17 signaling pathway. Our cohort also verified this point. In vitro experiments suggested that inhibition of S100A8 should promote cell apoptosis and suppress tumor growth. Single-cell RNA sequence analysis indicated that S100A8 might be associated with features of the tumor microenvironment (TME), and immune infiltration analyses discovered that S100A8 expression was involved in TME. In terms of drug screening, we predicted that many drugs were associated with preferable sensitivity.ConclusionElevated S100A8 expression is associated with a poor prognosis and immune infiltration in DLBCL. Inhibition of S100A8 could promote cell apoptosis and suppress tumor growth. Meanwhile, S100A8 has the potential to be a promising immunotherapeutic target for patients with DLBCL.
| S-EPMC10867108 | biostudies-literature
Project description:The outcomes of patients with diffuse large B-cell lymphoma (DLBCL) vary widely, and about 40% of them could not be cured by the standard first-line treatment, R-CHOP, which could be due to the high heterogeneity of DLBCL. Here, we aim to construct a prognostic model based on the genetic signature of metabolic heterogeneity of DLBCL to explore therapeutic strategies for DLBCL patients. Clinical and transcriptomic data of one training and four validation cohorts of DLBCL were obtained from the GEO database. Metabolic subtypes were identified by PAM clustering of 1,916 metabolic genes in the 7 major metabolic pathways in the training cohort. DEGs among the metabolic clusters were then analyzed. In total, 108 prognosis-related DEGs were identified. Through univariable Cox and LASSO regression analyses, 15 DEGs were used to construct a risk score model. The overall survival (OS) and progression-free survival (PFS) of patients with high risk were significantly worse than those with low risk (OS: HR 2.86, 95%CI 2.04–4.01, p < 0.001; PFS: HR 2.42, 95% CI 1.77–3.31, p < 0.001). This model was also associated with OS in the four independent validation datasets (GSE10846: HR 1.65, p = 0.002; GSE53786: HR 2.05, p = 0.02; GSE87371: HR 1.85, p = 0.027; GSE23051: HR 6.16, p = 0.007) and PFS in the two validation datasets (GSE87371: HR 1.67, p = 0.033; GSE23051: HR 2.74, p = 0.049). Multivariable Cox analysis showed that in all datasets, the risk model could predict OS independent of clinical prognosis factors (p < 0.05). Compared with the high-risk group, patients in the low-risk group predictively respond to R-CHOP (p = 0.0042), PI3K inhibitor (p < 0.05), and proteasome inhibitor (p < 0.05). Therefore, in this study, we developed a signature model of 15 DEGs among 3 metabolic subtypes, which could predict survival and drug sensitivity in DLBCL patients.
| S-EPMC9931744 | biostudies-literature