Dataset Information

Discovery of Prognostic Signature Genes for Overall Survival Prediction in Gastric Cancer.

ABSTRACT: Background:Gastric cancer (GC) is one of the most common malignant tumors in the digestive system with high mortality globally. However, the biomarkers that accurately predict the prognosis are still lacking. Therefore, it is important to screen for novel prognostic markers and therapeutic targets. Methods:We conducted differential expression analysis and survival analysis to screen out the prognostic genes. A stepwise method was employed to select a subset of genes in the multivariable Cox model. Overrepresentation enrichment analysis (ORA) was used to search for the pathways associated with poor prognosis. Results:In this study, we designed a seven-gene-signature-based Cox model to stratify the GC samples into high-risk and low-risk groups. The survival analysis revealed that the high-risk and low-risk groups exhibited significantly different prognostic outcomes in both the training and validation datasets. Specifically, CGB5, IGFBP1, OLFML2B, RAI14, SERPINE1, IQSEC2, and MPND were selected by the multivariable Cox model. Functionally, PI3K-Akt signaling pathway and platelet-derived growth factor receptor (PDGFR) were found to be hyperactive in the high-risk group. The multivariable Cox regression analysis revealed that the risk stratification based on the seven-gene-signature-based Cox model was independent of other prognostic factors such as TNM stages, age, and gender. Conclusion:In conclusion, we aimed at developing a model to predict the prognosis of gastric cancer. The predictive model could not only effectively predict the risk of GC but also be beneficial to the development of therapeutic strategies.

SUBMITTER: Meng C

PROVIDER: S-EPMC7468614 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Discovery of Prognostic Signature Genes for Overall Survival Prediction in Gastric Cancer.

Meng Changyuan C Xia Shusen S He Yi Y Tang Xiaolong X Zhang Guangjun G Zhou Tong T

Computational and mathematical methods in medicine 20200825

<h4>Background</h4>Gastric cancer (GC) is one of the most common malignant tumors in the digestive system with high mortality globally. However, the biomarkers that accurately predict the prognosis are still lacking. Therefore, it is important to screen for novel prognostic markers and therapeutic targets.<h4>Methods</h4>We conducted differential expression analysis and survival analysis to screen out the prognostic genes. A stepwise method was employed to select a subset of genes in the multiva ...[more]

PMID: 32908579

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Project description:Aims. This study is aimed at identifying a prognostic signature for cervical cancer. Main Methods. The gene expression data and clinical information of cervical cancer and normal cervical tissues were acquired from The Cancer Genome Atlas and from three datasets of the Gene Expression Omnibus database. DESeq2 and Limma were employed to screen differentially expressed genes (DEGs). The overlapping DEGs among all datasets were considered the final DEGs. Then, the functional enrichment analysis was performed. Moreover, the Cox proportional hazards regression was performed to establish a prognostic signature of the DEGs. The Kaplan-Meier analysis was applied to test the model. Relationships between gene expression and clinicopathological parameters in cervical cancer, including age, HPV status, histology, stage, and lymph node metastasis, were analysed by the chi-square test. The somatic mutations of these prognostic genes were assessed through cBioPortal. The robustness of the model was verified in another two independent validation cohorts. Key Findings. In total, 169 overlapping upregulated genes and 29 overlapping downregulated genes were identified in cervical cancer compared with normal cervical tissues. Functional enrichment analysis indicated that the DEGs were mainly enriched in DNA replication, the cell cycle, and the p53 signalling pathway. Finally, a 5-gene- (ITM2A, DSG2, SPP1, EFNA1, and MMP1) based prognostic signature was built. According to this model, each patient was given a prognostic-related risk value. The Kaplan-Meier analysis showed that a higher risk was related to worse overall survival in cervical cancer, with an area under the receiver operating characteristic curve of 0.811 for 15 years. The validity of this model in the prediction of cervical cancer outcome was verified in another two independent datasets. In addition, our study also found that the low expression of ITM2A was associated with cervical adenocarcinoma. Interestingly, DSG2 was associated with the HPV status of cervical cancer. Significance. Our study constructed a prognostic model in cervical cancer and discovered two novel genes, ITM2A and DSG2, associated with cervical carcinogenesis and survival.

Project description:BackgroundAs a serious challenge for public health, the prognosis of gastric cancer patients is still poor. The current study aimed to develop and validate a prognostic signature to predict the overall survival of gastric cancer patients.Patients and methodsThe dataset in the present study was obtained from The Cancer Genome Atlas database. The present study finally included 343 gastric cancer patients with information on long non-coding RNA (lncRNA) expression and overall survival.ResultsA prognostic model named Eleven-lncRNA signature was constructed according to the expression values of eleven prognostic lncRNA predictors identified by univariate and multivariate Cox regression model. According to time-dependent receiver operating characteristic curves, the Harrell's concordance indexes of Eleven-lncRNA signature were 0.764 (95% CI 0.720-0.808), 0.776 (95% CI 0.732-0.820), and 0.807 (95% CI 0.763-0.851) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively in the model group. In the validation group, the Harrell's concordance indexes of Eleven-lncRNA signature were 0.748 (95% CI 0.704-0.792), 0.794 (95% CI 0.750-0.838), and 0.798 (95% CI 0.754-0.842) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively. The gastric cancer patients (n=343) in the model group could be stratified into low-risk group (n=171) and high-risk group (n=172) according to the median of Eleven-lncRNA signature score. Kaplan-Meier survival curves showed that the mortality rate in the high-risk group was significantly poorer than that in the low-risk group (P<0.001).ConclusionThe present study constructed and validated a prognostic model named Eleven-lncRNA signature for preoperative individual mortality risk prediction in gastric cancer patients. This Eleven-lncRNA signature can predict the individual mortality risk of gastric cancer patients and is helpful in improving clinical decision making regarding individualized treatment.

Project description:BackgroundGastric cancer (GC) has a high mortality rate and is one of the most fatal malignant tumours. Male sex has been proven as an independent risk factor for GC. This study aimed to identify immune-related genes (IRGs) associated with the prognosis of male GC.MethodsRNA sequencing and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed IRGs between male GC and normal tissues were identified by integrated bioinformatics analysis. Univariate and multivariate Cox regression analyses were applied to screen survival-associated IRGs. Then, GC patients were separated into high- and low-risk groups based on the median risk score. Furthermore, a nomogram was constructed based on the TCGA dataset. The prognostic value of the risk signature model was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell's concordance index and calibration curves. In addition, the gene expression dataset from the Gene Expression Omnibus (GEO) was also downloaded for external validation. The relative proportions of 22 types of infiltrating immune cells in each male GC sample were evaluated using CIBERSORT.ResultsA total of 276 differentially expressed IRGs were screened, including 189 up-regulated and 87 down-regulated genes. Subsequently, a seven-IRGs signature (LCN12, CCL21, RNASE2, CGB5, NRG4, AGTR1 and NPR3) was identified to be significantly associated with the overall survival (OS) of male GC patients. Survival analysis indicated that patients in the high-risk group exhibited a poor clinical outcome. The results of multivariate analysis revealed that the risk score was an independent prognostic factor. The established nomogram could be used to evaluate the prognosis of individual male GC patients. Further analysis showed that the prognostic model had excellent predictive performance in both TCGA and validated cohorts. Besides, the results of tumour-infiltrating immune cell analysis indicated that the seven-IRGs signature could reflect the status of the tumour immune microenvironment.ConclusionsOur study developed a novel seven-IRGs risk signature for individualized survival prediction of male GC patients.

Project description:Importance:Breast cancer (BC), a common malignant tumor, ranks first among cancers in terms of morbidity and mortality among female patients. Currently, identifying effective prognostic models has a significant association with the prediction of the overall survival of patients with BC and guidance of clinicians in early diagnosis and treatment. Objectives:To identify a potential DNA repair-related prognostic signature through a comprehensive evaluation and to further improve the accuracy of prediction of the overall survival of patients with BC. Design, Setting, and Participants:In this prognostic study, conducted from October 9, 2019, to February 3, 2020, the gene expression profiles and clinical data of patients with BC were collected from The Cancer Genome Atlas database. This study consisted of a training set from The Cancer Genome Atlas database and 2 validation cohorts from the Gene Expression Omnibus, which included 1096 patients with BC. A prognostic signature based on 8 DNA repair-related genes (DRGs) was developed to predict overall survival among female patients with BC. Main Outcomes and Measures:Primary screening prognostic biomarkers were analyzed using univariate Cox proportional hazards regression analysis and the least absolute shrinkage and selection operator Cox proportional hazards regression. A risk model was completely established through multivariate Cox proportional hazards regression analysis. Finally, a prognostic nomogram, combining the DRG signature and clinical characteristics of patients, was constructed. To examine the potential mechanisms of the DRGs, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Results:In this prognostic study based on samples from 1096 women with BC (mean [SD] age, 59.6 [13.1] years), 8 DRGs (MDC1, RPA3, MED17, DDB2, SFPQ, XRCC4, CYP19A1, and PARP3) were identified as prognostic biomarkers. The time-dependent receiver operating characteristic curve analysis suggested that the 8-gene signature had a good predictive accuracy. In the training cohort, the areas under the curve were 0.708 for 3-year survival and 0.704 for 5-year survival. In the validation cohort, the areas under the curve were 0.717 for 3-year survival and 0.772 for 5-year survival in the GSE9893 data set and 0.691 for 3-year survival and 0.718 for 5-year survival in the GSE42568 data set. This DRG signature mainly involved some regulation pathways of vascular endothelial cell proliferation. Conclusions and Relevance:In this study, a prognostic signature using 8 DRGs was developed that successfully predicted overall survival among female patients with BC. This risk model provides new clinical evidence for the diagnostic accuracy and targeted treatment of BC.

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:BACKGROUND:The current Union International Committee on Cancer or the American Joint Committee on Cancer TNM stage system has shown valuable but insufficient estimation for subsets of gastric cancer and prediction for prognosis patients. Thus, there is an urgent need to identify diagnostic, prognostic, and predictive biomarkers to improve patients' outcomes. Our aim was to perform an integrative analysis on publicly available datasets to identify epigenetic changes that may play key role in the initiation and progression of gastric cancer, based on which we set to develop a DNA methylation signature to improve survival prediction of gastric cancer. RESULTS:A total of 340 methylation-related differentially expression genes (mrDEGs) were screened in gastric cancer patients from The Cancer Genome Atlas (TCGA) project. Pathway enrichment analysis revealed that they were involved in the biological process related to initiation and progression of gastric cancer. Based on the mrDEGs identified, we developed a DNA methylation signature consisting of ten gene members (SCNN1B, NFE2L3, CLDN2, RBPMS2, JPH2, GBP6, COL4A5, SMKR1, PPP1R14A, and ARL4D) according to their methylation ? value. This innovative DNA methylation signature was associated with cancer recurrence, while it showed independence of cancer recurrence and TNM stage for survival prediction. Combination of this DNA methylation signature and TNM stage improved overall survival prediction in the receiver operating characteristic analysis. We also verified that two individual genes (PPP1R14A and SCNN1B) of the identified prognostic signature were regulated by promoter region methylation in a panel of gastric cell lines. CONCLUSIONS:This study presents a powerful DNA methylation signature by performing analyses integrating multi-source data including transcriptome, methylome, and clinical outcome of gastric cancer patients from TCGA. The identified DNA methylation signature may be used to refine the current prognostic model and facilitate further stratification of patients in the future clinical trials. Further experimental studies are warranted to unveil the regulatory mechanism and functional role of all the individual genes of the DNA methylation signature. Also, clinical investigations in large GC patient cohorts are greatly needed to validate our findings.

Project description:BACKGROUND:Breast cancer is the most common malignancy in female patients worldwide. Because of its heterogeneity in terms of prognosis and therapeutic response, biomarkers with the potential to predict survival or assist in making treatment decisions in breast cancer patients are essential for an individualised therapy. Epigenetic alterations in the genome of the cancer cells, such as changes in DNA methylation pattern, could be a novel marker with an important role in the initiation and progression of breast cancer. METHOD:DNA methylation and RNA-seq datasets from The Cancer Genome Atlas (TCGA) were analysed using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox model. Applying gene ontology (GO) and single sample gene set enrichment analysis (ssGSEA) an epigenetic signature associated with the survival of breast cancer patients was constructed that yields the best discrimination between tumour and normal breast tissue. A predictive nomogram was built for the optimal strategy to distinguish between high- and low-risk cases. RESULTS:The combination of mRNA-expression and of DNA methylation datasets yielded a 13-gene epigenetic signature that identified subset of breast cancer patients with low overall survival. This high-risk group of tumor cases was marked by upregulation of known cancer-related pathways (e.g. mTOR signalling). Subgroup analysis indicated that this epigenetic signature could distinguish high and low-risk patients also in different molecular or histological tumour subtypes (by Her2-, EGFR- or ER expression or different tumour grades). Using Gene Expression Omnibus (GEO) the 13-gene signature was confirmed in four external breast cancer cohorts. CONCLUSION:An epigenetic signature was discovered that effectively stratifies breast cancer patients into low and high-risk groups. Since its efficiency appears independent of other known classifiers (such as staging, histology, metastasis status, receptor status), it has a high potential to further improve likely individualised therapy in breast cancer.

Dataset Information

Discovery of Prognostic Signature Genes for Overall Survival Prediction in Gastric Cancer.

Publications

Discovery of Prognostic Signature Genes for Overall Survival Prediction in Gastric Cancer.

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