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      Fifteen hub genes associated with progression and prognosis of clear cell renal cell carcinoma identified by coexpression analysis

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          Abstract

          Renal cell carcinoma (RCC) is the most common type of renal tumor, and the clear cell renal cell carcinoma (ccRCC) is the most frequent subtype. In this study, our aim is to identify potential biomarkers that could effectively predict the prognosis and progression of ccRCC. First, we used The Cancer Genome Atlas (TCGA) RNA-sequencing (RNA-seq) data of ccRCC to identify 2370 differentially expressed genes (DEGs). Second, the DEGs were used to construct a coexpression network by weighted gene coexpression network analysis (WGCNA). Moreover, we identified the yellow module, which was strongly related to the histologic grade and pathological stage of ccRCC. Then, the functional annotation of the yellow module and single-samples gene-set enrichment analysis of DEGs were performed and mainly enriched in cell cycle. Subsequently, 18 candidate hub genes were screened through WGCNA and protein-protein interaction (PPI) network analysis. After verification of TCGA's ccRCC data set, Gene Expression Omnibus (GEO) data set (GSE73731) and tissue validation, we finally identified 15 hub genes that can actually predict the progression of ccRCC. In addition, by using survival analysis, we found that patients of ccRCC with high expression of each hub gene were more likely to have poor prognosis than those with low expression. The receiver operating characteristic curve showed that each hub gene could effectively distinguish between localized and advanced ccRCC. In summary, our study indicates that 15 hub genes have great predictive value for the prognosis and progression of ccRCC, and may contribute to the exploration of the pathogenesis of ccRCC.

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          Most cited references23

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          Systematic determination of genetic network architecture.

          Technologies to measure whole-genome mRNA abundances and methods to organize and display such data are emerging as valuable tools for systems-level exploration of transcriptional regulatory networks. For instance, it has been shown that mRNA data from 118 genes, measured at several time points in the developing hindbrain of mice, can be hierarchically clustered into various patterns (or 'waves') whose members tend to participate in common processes. We have previously shown that hierarchical clustering can group together genes whose cis-regulatory elements are bound by the same proteins in vivo. Hierarchical clustering has also been used to organize genes into hierarchical dendograms on the basis of their expression across multiple growth conditions. The application of Fourier analysis to synchronized yeast mRNA expression data has identified cell-cycle periodic genes, many of which have expected cis-regulatory elements. Here we apply a systematic set of statistical algorithms, based on whole-genome mRNA data, partitional clustering and motif discovery, to identify transcriptional regulatory sub-networks in yeast-without any a priori knowledge of their structure or any assumptions about their dynamics. This approach uncovered new regulons (sets of co-regulated genes) and their putative cis-regulatory elements. We used statistical characterization of known regulons and motifs to derive criteria by which we infer the biological significance of newly discovered regulons and motifs. Our approach holds promise for the rapid elucidation of genetic network architecture in sequenced organisms in which little biology is known.
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            Is Open Access

            Application of ggplot2 to Pharmacometric Graphics

            Visualization is a powerful mechanism for extracting information from data. ggplot2 is a contributed visualization package in the R programming language, which creates publication-quality statistical graphics in an efficient, elegant, and systematic manner. This article summarizes key features of the package with examples from pharmacometrics and pointers to available resources for learning ggplot2.
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              Correlating transcriptional networks to breast cancer survival: a large-scale coexpression analysis.

              Weighted gene coexpression network analysis (WGCNA) is a powerful 'guilt-by-association'-based method to extract coexpressed groups of genes from large heterogeneous messenger RNA expression data sets. We have utilized WGCNA to identify 11 coregulated gene clusters across 2342 breast cancer samples from 13 microarray-based gene expression studies. A number of these transcriptional modules were found to be correlated to clinicopathological variables (e.g. tumor grade), survival endpoints for breast cancer as a whole (disease-free survival, distant disease-free survival and overall survival) and also its molecular subtypes (luminal A, luminal B, HER2+ and basal-like). Examples of findings arising from this work include the identification of a cluster of proliferation-related genes that when upregulated correlated to increased tumor grade and were associated with poor survival in general. The prognostic potential of novel genes, for example, ubiquitin-conjugating enzyme E2S (UBE2S) within this group was confirmed in an independent data set. In addition, gene clusters were also associated with survival for breast cancer molecular subtypes including a cluster of genes that was found to correlate with prognosis exclusively for basal-like breast cancer. The upregulation of several single genes within this coexpression cluster, for example, the potassium channel, subfamily K, member 5 (KCNK5) was associated with poor outcome for the basal-like molecular subtype. We have developed an online database to allow user-friendly access to the coexpression patterns and the survival analysis outputs uncovered in this study (available at http://glados.ucd.ie/Coexpression/).
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                Author and article information

                Journal
                Journal of Cellular Physiology
                J Cell Physiol
                Wiley
                0021-9541
                1097-4652
                December 07 2018
                July 2019
                November 11 2018
                July 2019
                : 234
                : 7
                : 10225-10237
                Affiliations
                [1 ]Department of UrologyZhongnan Hospital of Wuhan UniversityWuhan China
                [2 ]Department of Biological RepositoriesZhongnan Hospital of Wuhan UniversityWuhan China
                [3 ]Human Genetics Resource Preservation Center of Hubei ProvinceWuhan China
                [4 ]Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan UniversityWuhan China
                [5 ]Greenebaum Cancer Center, School of Medicine, University of MarylandBaltimore Maryland
                [6 ]Department of UrologyMassachusetts General Hospital, Harvard Medical SchoolBoston Massachusetts
                [7 ]Medical Research Institute, Wuhan UniversityWuhan China
                Article
                10.1002/jcp.27692
                30417363
                fe7d4b70-cd6f-4b86-ad0f-a94adcb139f6
                © 2019

                http://onlinelibrary.wiley.com/termsAndConditions#vor

                http://doi.wiley.com/10.1002/tdm_license_1.1

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