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Gene expression profiles analysis identifies a novel two-gene signature to predict overall survival in diffuse large B-cell lymphoma.

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy, however, specific tumor-associated genes and signaling pathways are yet to be deciphered. Differentially expressed genes (DEGs) were computed based on gene expression profiles from GSE32018, GSE56315, and The Cancer Genome Atlas (TCGA) DLBC. Overlapping DEGs were then evaluated for gene ontology (GO), pathways enrichment, DNA methylation, protein-protein interaction (PPI) network analysis as well as survival analysis. Seventy-four up-regulated and 79 down-regulated DEGs were identified. From PPI network analysis, majority of the DEGs were involved in cell cycle, oocyte meiosis, and epithelial-to-mesenchymal transition (EMT) pathways. Six hub genes including CDC20, MELK, PBK, prostaglandin D2 synthase (PTGDS), PCNA, and CDK1 were selected using the Molecular Complex Detection (MCODE). CDC20 and PTGDS were able to predict overall survival (OS) in TCGA DLBC and in an additional independent cohort GSE31312. Furthermore, CDC20 DNA methylation negatively regulated CDC20 expression and was able to predict OS in DLBCL. A two-gene panel consisting of CDC20 and PTGDS had a better prognostic value compared with CDC20 or PTGDS alone in the TCGA cohort (P=0.026 and 0.039). Overall, the present study identified a set of novel genes and pathways that may play a significant role in the initiation and progression of DLBCL. In addition, CDC20 and PTGDS will provide useful guidance for therapeutic applications.

SUBMITTER: Sun C

PROVIDER: S-EPMC6328866 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Gene expression profiles analysis identifies a novel two-gene signature to predict overall survival in diffuse large B-cell lymphoma.

Sun Chengtao C Cheng Xianfeng X Wang Chaoyu C Wang Xi X Xia Bing B Zhang Yizhuo Y

Bioscience reports 20190103 1

Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy, however, specific tumor-associated genes and signaling pathways are yet to be deciphered. Differentially expressed genes (DEGs) were computed based on gene expression profiles from GSE32018, GSE56315, and The Cancer Genome Atlas (TCGA) DLBC. Overlapping DEGs were then evaluated for gene ontology (GO), pathways enrichment, DNA methylation, protein-protein interaction (PPI) network analysis as well as survival analysi ...[more]

PMID: 30393234

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Project description:BackgroundWith the improvement of clinical treatment outcomes in diffuse large B cell lymphoma (DLBCL), the high rate of relapse in DLBCL patients is still an established barrier, as the therapeutic strategy selection based on potential targets remains unsatisfactory. Therefore, there is an urgent need in further exploration of prognostic biomarkers so as to improve the prognosis of DLBCL.MethodsThe univariable and multivariable Cox regression models were employed to screen out gene signatures for DLBCL overall survival (OS) prediction. The differential expression analysis was used to identify representative genes in high-risk and low-risk groups, respectively, where student t test and fold change were implemented. The functional difference between the high-risk and low-risk groups was identified by the gene set enrichment analysis.ResultsWe conducted a systematic data analysis to screen the candidate genes significantly associated with OS of DLBCL in three NCBI Gene Expression Omnibus (GEO) datasets. To construct a prognostic model, five genes (CEBPA, CYP27A1, LST1, MREG, and TARP) were then screened and tested using the multivariable Cox model and the stepwise regression method. Kaplan-Meier curve confirmed the good predictive performance of this five-gene Cox model. Thereafter, the prognostic model and the expression levels of the five genes were validated by means of an independent dataset. High expression levels of these five genes were significantly associated with favorable prognosis in DLBCL, both in training and validation datasets. Additionally, further analysis revealed the independent value and superiority of this prognostic model in risk prediction. Functional enrichment analysis revealed some vital pathways responsible for unfavorable outcome and potential therapeutic targets in DLBCL.ConclusionWe developed a five-gene Cox model for the clinical outcome prediction of DLBCL patients. Meanwhile, potential drug selection using this model can help clinicians to improve the clinical practice for the benefit of patients.

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.

Dataset Information

Gene expression profiles analysis identifies a novel two-gene signature to predict overall survival in diffuse large B-cell lymphoma.

Publications

Gene expression profiles analysis identifies a novel two-gene signature to predict overall survival in diffuse large B-cell lymphoma.

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