Abstract
Over 50% of diffuse large B-cell lymphoma (DLBCL) patients are diagnosed at an advanced stage. Although there are a few therapeutic strategies for DLBCL, most of them are more effective in limited-stage cancer patients. The prognosis of patients with advanced-stage DLBCL is usually poor with frequent recurrence and metastasis. In this study, we aimed to identify gene expression and network differences between limited- and advanced-stage DLBCL patients, with the goal of identifying potential agents that could be used to relieve the severity of DLBCL. Specifically, RNA sequencing data of DLBCL patients at different clinical stages were collected from the cancer genome atlas (TCGA). Differentially expressed genes were identified using DESeq2, and then, weighted gene correlation network analysis (WGCNA) and differential module analysis were performed to find variations between different stages. In addition, important genes were extracted by key driver analysis, and potential agents for DLBCL were identified according to gene-expression perturbations and the Crowd Extracted Expression of Differential Signatures (CREEDS) drug signature database. As a result, 20 up-regulated and 73 down-regulated genes were identified and 79 gene co-expression modules were found using WGCNA, among which, the thistle1 module was highly related to the clinical stage of DLBCL. KEGG pathway and GO enrichment analyses of genes in the thistle1 module indicated that DLBCL progression was mainly related to the NOD-like receptor signaling pathway, neutrophil activation, secretory granule membrane, and carboxylic acid binding. A total of 47 key drivers were identified through key driver analysis with 11 up-regulated key driver genes and 36 down-regulated key diver genes in advanced-stage DLBCL patients. Five genes (MMP1, RAB6C, ACCSL, RGS21 and MOCOS) appeared as hub genes, being closely related to the occurrence and development of DLBCL. Finally, both differentially expressed genes and key driver genes were subjected to CREEDS analysis, and 10 potential agents were predicted to have the potential for application in advanced-stage DLBCL patients. In conclusion, we propose a novel pipeline to utilize perturbed gene-expression signatures during DLBCL progression for identifying agents, and we successfully utilized this approach to generate a list of promising compounds.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed non-Hodgkin lymphoma (NHL), representing approximately 25% of new NHL cases each year in the United States (Liu and Barta, 2019)
For the purpose of developing new agents that could be utilized in combination with R- CHOP backbones to treat advanced stage DLBCL patients, we proposed a new method of drug repurposing based on gene expression and network perturbation (Figure 1)
A wealth of studies has focused on targeted therapies based on the molecular classification of DLBCL, the clinical stage of DLBCL remains an important factor for choosing an appropriate treatment regime
Summary
Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed non-Hodgkin lymphoma (NHL), representing approximately 25% of new NHL cases each year in the United States (Liu and Barta, 2019). Advanced-stage DLBCL patients were more likely to express higher levels of CD30 (Rodrigues-Fernandes et al, 2021) and CD25 (Oka et al, 2020), both of which are biomarkers of B-cell activation. The pattern of late disease relapses observed in advanced stage DLBCL cases was different from that of limited-stage cases, further corroborating that limited and advanced stage DLBCL were biologically heterogeneous (Hoiland et al, 2020). All of these observations prompted us to treat advanced- and limited-stage DLBCL with different strategies, better tailoring for their specific biological and clinical characteristics
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