Retrospective Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Jun 26, 2021; 9(18): 4585-4598
Published online Jun 26, 2021. doi: 10.12998/wjcc.v9.i18.4585
Evaluation of a five-gene signature associated with stromal infiltration for diffuse large B-cell lymphoma
Ying-Yu Nan, Wen-Jun Zhang, De-Hong Huang, Qi-Ying Li, Yang Shi, Tao Yang, Xi-Ping Liang, Chun-Yan Xiao, Bing-Ling Guo, Ying Xiang
Ying-Yu Nan, Wen-Jun Zhang, De-Hong Huang, Qi-Ying Li, Yang Shi, Tao Yang, Xi-Ping Liang, Chun-Yan Xiao, Bing-Ling Guo, Ying Xiang, Department of Hematology, Chongqing University Cancer Hospital, Chongqing 400030, China
Author contributions: Xiang Y conceived and designed the study; Nan YY, Zhang WJ and Huang DH conducted the experiments, data analysis and manuscript drafting, and the three authors contributed equally to the study; Yang T performed the statistical analyses; Li QY, Shi Y, Liang XP, Xiao CY and Guo BL participated intellectual discussions and revised the manuscript; All authors reviewed and approved the final manuscript.
Supported by the Natural Science Foundation of Chongqing, No. cstc2019jcyj-msxmX0793.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Chongqing University Cancer Hospital.
Informed consent statement: The patients were not required to give informed consent to participate in this study because the analysis used anonymous data obtained from an archival database.
Conflict-of-interest statement: All authors declare having no conflict of interests.
Data sharing statement: The supporting information is provided along with the BPG online publication, and no additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ying Xiang, MD, MSc, Chief Doctor, Department of Hematology, Chongqing University Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing 400030, China. xiangying0331@163.com
Received: November 16, 2020
Peer-review started: November 16, 2020
First decision: January 17, 2021
Revised: January 26, 2021
Accepted: February 24, 2021
Article in press: February 24, 2021
Published online: June 26, 2021
Abstract
BACKGROUND

Diffuse large B-cell lymphoma (DLBCL) is a common non-Hodgkin lymphoma. The development of immunotherapy greatly improves the patient prognosis but there are some exceptions. Thus, screening for better biomarkers for prognostic evaluation could contribute to the treatment of DLBCL patients.

AIM

To screen the novel mediators involved in the development of DLBCL.

METHODS

The GSE60 dataset was applied to identify the differentially expressed genes (DEGs) in DLBCL, and the principal components analysis plot was used to determine the quality of the included samples. The protein-protein interactions were analyzed by the STRING tool. The key hub genes were entered into to the GEPIA database to determine their expressions in DLBCL. Furthermore, these hub gene alterations were analyzed in cBioportal. The UALCAN portal was employed to analyze the expression of the hub genes in different stages of DLBCL. The Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data Score was conducted to evaluate the correlation between the gene expression and tumor purity. The gene-gene correlation analysis was conducted in the GEPIA. The stromal score analysis was conducted in TIMER to confirm the correlation between the gene expression and infiltrated stromal cells. The correlation between the indicated genes and infiltration level of cancer-associated fibroblasts (CAFs) was also completed in TIMER with two methods, MCP-Counter and Tumor immune dysfunction and exclusion. The correlation between fibronectin (FN1) protein level and secreted protein acidic and cysteine-rich (SPARC) messenger ribonucleic acid expression was confirmed in the cBioportal.

RESULTS

The top 20 DEGs in DLBCL were identified, and the principal components analysis plot confirmed the quality of the significant DEGs. The pairwise correlation coefficient analysis among all samples showed that these DEGs have a certain co-expression pattern. The DEGs were subjected to STRING to identify the hub genes, alpha-2-macroglobulin (A2M), cathepsin B (CTSB), FN1, matrix metallopeptidase 9 (MMP9), and SPARC. The five hub genes were confirmed to be overexpressed in DLBCL. The cBioportal portal detected these five hub genes that had gene alteration, including messenger ribonucleic acid high amplification and missense mutation, and the gene alteration percentages of A2M, FN1, CTSB, MMP9, and SPARC were 5%, 8%, 5%, 2.7%, and 5%, respectively. Furthermore, the five hub genes had a potential positive correlation with tumor stage. The correlation analysis between the five genes and tumor purity confirmed that the five genes were overexpressed in DLBCL and had a positive correlation with the development of DLBCL. More interestingly, the five genes had a significant correlation with the stromal infiltration scores. The correlation analysis between the fives genes and CAFs also showed a significant value, among which the top two genes, FN1 and SPARC, had a remarkable co-expression pattern.

CONCLUSION

The top DEGs were identified, and the five hub genes were overexpressed in DLBCL. Furthermore, the gene alterations were confirmed and the positive correlation with tumor purity revealed the overexpression of the five genes and close association with the development of DLBCL. More interestingly, the five genes were positively correlated with stromal infiltration, especially in CAFs. The top two genes, FN1 and SPARC, showed a co-expression pattern, which indicates their potential as novel therapeutic targets for DLBCL.

Keywords: Diffuse large B-cell lymphoma, Co-expression, Overexpression, Stromal score, Cancer-associated fibroblasts, Therapeutic target

Core Tip: In this project, we identified five genes that were overexpressed in diffuse large B-cell lymphoma (DLBCL), and the five gene signatures were closely associated with the development of DLBCL. More importantly, the five genes were positively correlated with stromal cell infiltration, especially in cancer-associated fibroblasts. Taken together, these genes might be novel therapeutic targets for DLBCL.