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Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis.

ABSTRACT: BACKGROUND:Papillary thyroid carcinoma (PTC), which is the most common endocrine malignancy, has been steadily increasing worldwide in incidence over the years, while mechanisms underlying the pathogenesis and diagnostic for PTC are incomplete. The purpose of this study is to identify potential biomarkers for diagnosis of PTC, and provide new insights into pathogenesis of PTC. METHODS:Based on weighted gene co-expression network analysis, Robust Rank Aggregation, functional annotation, GSEA and DNA methylation, were employed for investigating potential biomarkers for diagnosis of PTC. RESULTS:Black and turquoise modules were identified in the gene co-expression network constructed by 1807 DEGs that from 6 eligible gene expression profiles of Gene Expression Omnibus database based on Robust Rank Aggregation and weighted gene co-expression network analysis. Hub genes were significantly down-regulated and the expression levels of the hub genes were different in different stages in hub gene verification. ROC curves indicated all hub genes had good diagnostic value for PTC (except for ABCA6 AUC?=?89.5%, the 15 genes with AUC?>?90%). Methylation analysis showed that hub gene verification ABCA6, ACACB, RMDN1 and TFPI were identified as differentially methylated genes, and the decreased expression level of these genes may relate to abnormal DNA methylation. Moreover, the expression levels of 8 top hub genes were correlated with tumor purity and tumor-infiltrating immune cells. These findings, including functional annotations and GSEA provide new insights into pathogenesis of PTC. CONCLUSIONS:The hub genes and methylation of hub genes may as potential biomarkers provide new insights for diagnosis of PTC, and all these findings may be the direction to study the mechanisms underlying of PTC in the future.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7161219 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis.

Liu Yang Y Chen Ting-Yu TY Yang Zhi-Yan ZY Fang Wei W Wu Qian Q Zhang Chao C

Journal of translational medicine 20200416 1

<h4>Background</h4>Papillary thyroid carcinoma (PTC), which is the most common endocrine malignancy, has been steadily increasing worldwide in incidence over the years, while mechanisms underlying the pathogenesis and diagnostic for PTC are incomplete. The purpose of this study is to identify potential biomarkers for diagnosis of PTC, and provide new insights into pathogenesis of PTC.<h4>Methods</h4>Based on weighted gene co-expression network analysis, Robust Rank Aggregation, functional annota ...[more]

PMID: 32299435

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Project description:BackgroundBioinformatics provides a valuable tool to explore the molecular mechanisms underlying pathogenesis of hepatocellular carcinoma (HCC). To improve prognosis of patients, identification of robust biomarkers associated with the pathogenic pathways of HCC remains an urgent research priority.MethodsWe employed the Robust Rank Aggregation method to integrate nine qualified HCC datasets from the Gene Expression Omnibus. A robust set of differentially expressed genes (DEGs) between tumor and normal tissue samples were screened. Weighted gene co-expression network analysis was applied to cluster DEGs and the key modules related to clinical traits identified. Based on network topology analysis, novel risk genes derived from key modules were mined and biological verification performed. The potential functions of these risk genes were further explored with the aid of miRNA-mRNA regulatory networks. Finally, the prognostic ability of these genes was assessed by constructing a clinical prediction model.ResultsTwo key modules showed significant association with clinical traits. In combination with protein-protein interaction analysis, 29 hub genes were identified. Among these genes, 19 from one module showed a pattern of upregulation in HCC and were associated with the tumor node metastasis stage, and 10 from the other module displayed the opposite trend. Survival analyses indicated that all these genes were significantly related to patient prognosis. Based on the miRNA-mRNA regulatory network, 29 genes strongly linked to tumor activity were identified. Notably, five of the novel risk genes, ABAT, DAO, PCK2, SLC27A2, and HAO1, have rarely been reported in previous studies. Gene set enrichment analysis for each gene revealed regulatory roles in proliferation and prognosis of HCC. Least absolute shrinkage and selection operator regression analysis further validated DAO, PCK2, and HAO1 as prognostic factors in an external HCC dataset.ConclusionAnalysis of multiple datasets combined with global network information presents a successful approach to uncover the complex biological mechanisms of HCC. More importantly, this novel integrated strategy facilitates identification of risk hub genes as candidate biomarkers for HCC, which could effectively guide clinical treatments.

Project description:Background The genes and genetic mechanisms underlying the occurrence and progression of papillary thyroid carcinoma (PTC) are still unknown. This study aimed to find candidate genes related to the pathogenesis and progression of PTC. Methods RNA sequencing (RNA-seq) data of PTC and normal tissues were downloaded from The Cancer Genome Atlas (TCGA) database with clinical stage data to form a test, validation, and clinical-stage data matrix. We used the test data set to analyze differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) to find those gene clusters highly correlated with PTC. We then verified the expression of genes in the interested modules using the validation matrix. The quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the reliability of the expression of selected genes. Five key genes (GDF15, LCN2, KCNN4, SH3BGRL3, and MMP2) were used to analyze the connection between gene expression and the American Joint Committee on Cancer (AJCC) stage. The upregulated and downregulated DEGs, along with the modules of interest, were subjected to Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Results We used WGCNA to find two modules of interest, the yellow module, which was positively associated with PTC, and the blue module, which was negatively correlated with PTC. Four genes (GDF15, LCN2, KCNN4, and SH3BGRL3) from the yellow module were determined to be highly expressed in PTC in the test data matrix and were verified in both the validation data matrix and quantitative real-time PCR, which indicated that these four genes were highly correlated with the occurrence of the PTC. Furthermore, these four genes also had a significantly higher expression in the advanced levels of pathological T, N, and AJCC stage, meaning that they were correlated with the progression of PTC. Genes in the yellow module and upregulated DEGs were significantly enriched in three vital signaling pathways, including focal adhesion, extracellular matrix (ECM)-receptor interaction, and the PI3K-Akt signaling pathway. Conclusions Four candidate genes (GDF15, LCN2, KCNN4, and SH3BGRL3) may be potential biomarkers for the PTC’s pathogenesis and may be useful for predicting the disease stage.

Project description:The present study aimed to screen all types of RNAs involved in the development of papillary thyroid carcinoma (PTC). RNA?sequencing data of PTC and normal samples were used for screening differentially expressed (DE) microRNAs (DE?miRNAs), long non?coding RNAs (DE?lncRNAs) and genes (DEGs). Subsequently, lncRNA?miRNA, miRNA?gene (that is, miRNA?mRNA) and gene?gene interaction pairs were extracted and used to construct regulatory networks. Feature genes in the miRNA?mRNA network were identified by topological analysis and recursive feature elimination analysis. A support vector machine (SVM) classifier was built using 15 feature genes, and its classification effect was validated using two microarray data sets that were downloaded from the Gene Expression Omnibus (GEO) database. In addition, Gene Ontology function and Kyoto Encyclopedia Genes and Genomes pathway enrichment analyses were conducted for genes identified in the ceRNA network. A total of 506 samples, including 447 tumor samples and 59 normal samples, were obtained from The Cancer Genome Atlas (TCGA); 16 DE?lncRNAs, 917 DEGs and 30 DE?miRNAs were screened. The miRNA?mRNA regulatory network comprised 353 nodes and 577 interactions. From these data, 15 feature genes with high predictive precision (>95%) were extracted from the network and were used to form an SVM classifier with an accuracy of 96.05% (486/506) for PTC samples downloaded from TCGA, and accuracies of 96.81 and 98.46% for GEO downloaded data sets. The ceRNA regulatory network comprised 596 lines (or interactions) and 365 nodes. Genes in the ceRNA network were significantly enriched in 'neuron development', 'differentiation', 'neuroactive ligand?receptor interaction', 'metabolism of xenobiotics by cytochrome P450', 'drug metabolism' and 'cytokine?cytokine receptor interaction' pathways. Hox transcript antisense RNA, miRNA?206 and kallikrein?related peptidase 10 were nodes in the ceRNA regulatory network of the selected feature gene, and they may serve import roles in the development of PTC.

Dataset Information

Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis.

Publications

Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis.

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