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Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis
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 frequen...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551569/ https://www.ncbi.nlm.nih.gov/pubmed/34721544 http://dx.doi.org/10.3389/fgene.2021.756784 |
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author | Xiang, Chenxi Ni, Huimin Wang, Zhina Ji, Binbin Wang, Bo Shi, Xiaoli Wu, Wanna Liu, Nian Gu, Ying Ma, Dongshen Liu, Hui |
author_facet | Xiang, Chenxi Ni, Huimin Wang, Zhina Ji, Binbin Wang, Bo Shi, Xiaoli Wu, Wanna Liu, Nian Gu, Ying Ma, Dongshen Liu, Hui |
author_sort | Xiang, Chenxi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8551569 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85515692021-10-29 Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis Xiang, Chenxi Ni, Huimin Wang, Zhina Ji, Binbin Wang, Bo Shi, Xiaoli Wu, Wanna Liu, Nian Gu, Ying Ma, Dongshen Liu, Hui Front Genet Genetics 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. Frontiers Media S.A. 2021-10-14 /pmc/articles/PMC8551569/ /pubmed/34721544 http://dx.doi.org/10.3389/fgene.2021.756784 Text en Copyright © 2021 Xiang, Ni, Wang, Ji, Wang, Shi, Wu, Liu, Gu, Ma and Liu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Xiang, Chenxi Ni, Huimin Wang, Zhina Ji, Binbin Wang, Bo Shi, Xiaoli Wu, Wanna Liu, Nian Gu, Ying Ma, Dongshen Liu, Hui Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis |
title | Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis |
title_full | Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis |
title_fullStr | Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis |
title_full_unstemmed | Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis |
title_short | Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis |
title_sort | agent repurposing for the treatment of advanced stage diffuse large b-cell lymphoma based on gene expression and network perturbation analysis |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551569/ https://www.ncbi.nlm.nih.gov/pubmed/34721544 http://dx.doi.org/10.3389/fgene.2021.756784 |
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