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pmid:30405856
Identification of Core Biomarkers Associated with Outcome in Glioma: Evidence from Bioinformatics Analysis.
Rong-Xin Geng · Ning Li · Yang Xu · Jun-Hui Liu · Fan-En Yuan · Qian Sun · Bao-Hui Liu · Qian-Xue Chen
Disease markers · 2018 doi:10.1155/2018/3215958
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Complete file
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We chose a gene expression profile of GSE66354 from GEO database to search core biomarkers during the occurrence and development of glioma. A total of 149 samples, involving 136 glioma and 13 normal brain tissues, were enrolled in this article. 1980 differentially expressed genes (DEGs) including 697 upregulated genes and 1283 downregulated genes between glioma patients and healthy individuals were selected using GeoDiver and GEO2R tool. Then, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) plug-in was employed to imagine protein-protein interaction (PPI) of these DEGs. The upregulated genes were enriched in cell cycle, ECM-receptor interaction, and p53 signaling pathway, while the downregulated genes were enriched in retrograde endocannabinoid signaling, glutamatergic synapse, morphine addiction, GABAergic synapse, and calcium signaling pathway. Subsequently, 4 typical modules were discovered by the PPI network utilizing MCODE software. Besides, 15 hub genes were chosen according to the degree of connectivity, including TP53, CDK1, CCNB1, and CCNB2, the Kaplan-Meier analysis of which was further identified. In conclusion, this bioinformatics analysis indicated that DEGs and core genes, such as TP53, might influence the development of glioma, especially in tumor proliferation, which were expected to be promising biomarkers for diagnosis and treatment of glioma.", "claims": [{"id": "claim-method", "statement": "GeoDiver used the limma R package to identify differentially expressed genes by fitting a linear model to each gene, which estimated the fold change in expression while accounting for standard errors by applying empirical Bayes smoothing.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30405856", "locator": "sections[13] \"4.2. 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Identification of DEGs and Hub Genes", "row_count": 16, "column_count": 3}, "table": {"label": "Table 1", "caption": "Top 15 hub genes with higher degree of connectivity.", "rows": [["Gene", "Degree of connectivity", "Adjusted p value"], ["TP53", "183", "1.53E − 15"], ["TOP2A", "166", "5.17E − 13"], ["CDK1", "146", "3.55E − 17"], ["PHLPP2", "139", "5.44E − 17"], ["DLG4", "124", "4.68E − 18"], ["CCNB1", "115", "3.09E − 05"], ["MYC", "115", "2.43E − 04"], ["CDC20", "111", "3.57E − 04"], ["CCNA2", "107", "5.72E − 05"], ["NDC80", "105", "2.00E − 10"], ["AURKA", "105", "5.00E − 05"], ["BIRC5", "103", "6.26E − 07"], ["CCNB2", "102", "1.70E − 08"], ["KIF11", "102", "5.41E − 11"], ["MAD2L1", "101", "2.98E − 06"]], "row_count": 16, "column_count": 3, "numeric_cells": 34, "header_rows": 1, "locator": "section[3]/table-wrap[1]#tab1"}}, {"id": "asset:table:pmid:30405856:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:f9c76cd5206711dc4a96bbae5c89932b54f109cdf9aa8d1fe88a8d909d9145f4", "bytes": 3360, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[4]/table-wrap[1]#tab2", "version": null, "note": "Gene ontology analysis of differentially expressed genes associated with glioma.", "structure": {"pmcid": "PMC6199874", "section_index": 4, "section_title": "2.2. GO Function and KEGG Pathway Analysis of DEGs", "row_count": 32, "column_count": 7}, "table": {"label": "Table 2", "caption": "Gene ontology analysis of differentially expressed genes associated with glioma.", "rows": [["Expression", "Category", "Term", "Count", "Ratio (%)", "p value", "FDR"], ["Upregulated", "GOTERM_BP_FAT", "GO:0000278_mitotic cell cycle", "105", "15.21739", "1.34E − 26", "2.60E − 23"], ["GOTERM_BP_FAT", "GO:1903047_mitotic cell cycle process", "100", "14.49275", "1.81E − 26", "3.51E − 23"], ["GOTERM_BP_FAT", "GO:0022402_cell cycle process", "120", "17.3913", "1.00E − 22", "1.94E − 19"], ["GOTERM_BP_FAT", "GO:0007067_mitotic nuclear division", "62", "8.985507", "1.10E − 21", "2.14E − 18"], ["GOTERM_BP_FAT", "GO:0051301_cell division", "71", "10.28986", "5.72E − 21", "1.11E − 17"], ["GOTERM_MF_FAT", "GO:0005201_extracellular matrix structural constituent", "15", "2.173913", "2.78E − 07", "4.37E − 04"], ["GOTERM_MF_FAT", "GO:0015026_coreceptor activity", "9", "1.304348", "2.11E − 05", "3.32E − 02"], ["GOTERM_MF_FAT", "GO:0017147_Wnt protein binding", "8", "1.15942", "4.31E − 05", "6.79E − 02"], ["GOTERM_MF_FAT", "GO:0003777_microtubule motor activity", "12", "1.73913", "4.41E − 05", "6.93E − 02"], ["GOTERM_MF_FAT", "GO:0019838_growth factor binding", "15", "2.173913", "5.77E − 05", "9.08E − 02"], ["GOTERM_CC_FAT", "GO:0044420_extracellular matrix component", "36", "5.217391", "1.74E − 21", "2.56E − 18"], ["GOTERM_CC_FAT", "GO:0005578_proteinaceous extracellular matrix", "55", "7.971014", "3.38E − 19", "4.99E − 16"], ["GOTERM_CC_FAT", "GO:0031012_extracellular matrix", "65", "9.42029", "1.05E − 17", "1.54E − 14"], ["GOTERM_CC_FAT", "GO:0005604_basement membrane", "26", "3.768116", "3.08E − 15", "4.59E − 12"], ["GOTERM_CC_FAT", "GO:0015630_microtubule cytoskeleton", "93", "13.47826", "2.04E − 14", "3.01E − 11"], [""], ["Downregulated", "GOTERM_BP_FAT", "GO:0099536_synaptic signaling", "194", "15.39683", "1.23E − 90", "2.39E − 87"], ["GOTERM_BP_FAT", "GO:0098916_anterograde trans-synaptic signaling", "194", "15.39683", "1.23E − 90", "2.39E − 87"], ["GOTERM_BP_FAT", "GO:0099537_trans-synaptic signaling", "194", "15.39683", "1.23E − 90", "2.39E − 87"], ["GOTERM_BP_FAT", "GO:0007268_chemical synaptic transmission", "194", "15.39683", "1.23E − 90", "2.39E − 87"], ["GOTERM_BP_FAT", "GO:0007399_nervous system development", "324", "25.71429", "2.19E − 60", "4.25E − 57"], ["GOTERM_MF_FAT", "GO:0022836_gated channel activity", "95", "7.539683", "1.44E − 38", "2.37E − 35"], ["GOTERM_MF_FAT", "GO:0005216_ion channel activity", "101", "8.015873", "2.22E − 33", "3.67E − 30"], ["GOTERM_MF_FAT", "GO:0022838_substrate-specific channel activity", "101", "8.015873", "5.72E − 32", "9.44E − 29"], ["GOTERM_MF_FAT", "GO:0015267_channel activity", "103", "8.174603", "1.31E − 30", "2.16E − 27"], ["GOTERM_MF_FAT", "GO:0022803_passive transmembrane transporter activity", "103", "8.174603", "1.57E − 30", "2.59E − 27"], ["GOTERM_CC_FAT", "GO:0045202_synapse", "232", "18.4127", "9.60E − 105", "1.43E − 101"], ["GOTERM_CC_FAT", "GO:0097458_neuron part", "306", "24.28571", "1.50E − 104", "2.23E − 101"], ["GOTERM_CC_FAT", "GO:0044456_synapse part", "202", "16.03175", "2.51E − 97", "3.73E − 94"], ["GOTERM_CC_FAT", "GO:0043005_neuron projection", "232", "18.4127", "1.87E − 80", "2.79E − 77"], ["GOTERM_CC_FAT", "GO:0030424_axon", "131", "10.39683", "4.44E − 58", "6.61E − 55"]], "row_count": 32, "column_count": 7, "numeric_cells": 150, "header_rows": 1, "locator": "section[4]/table-wrap[1]#tab2"}}, {"id": "asset:table:pmid:30405856:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:25113daee07e1d2764eb34721c2b7648e85777e4fba3c5297979ab276b43d606", "bytes": 3235, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[4]/table-wrap[2]#tab3", "version": null, "note": "KEGG pathway analysis of differentially expressed genes associated with glioma.", "structure": {"pmcid": "PMC6199874", "section_index": 4, "section_title": "2.2. GO Function and KEGG Pathway Analysis of DEGs", "row_count": 12, "column_count": 7}, "table": {"label": "Table 3", "caption": "KEGG pathway analysis of differentially expressed genes associated with glioma.", "rows": [["Expression", "Term", "Count", "Ratio (%)", "p value", "Genes", "FDR"], ["Upregulated", "hsa04110: cell cycle", "23", "3.333333", "3.25E − 11", "CDK1, E2F5, TP53, TTK, CHEK1, CDC20, CDK6, MCM2, SFN, CDK4, TGFB1, WEE1, CDK2, MCM5, CCNB1, CCND1, MAD2L1, CCNB2, CDKN2C, BUB1, BUB1B, MYC, CCNA2", "4.06E − 08"], ["hsa04512: ECM-receptorinteraction", "19", "2.753623", "1.55E − 10", "TNC, COL3A1, HSPG2, ITGA2, ITGA4, COL4A6, COL5A1, HMMR, LAMA2, LAMA1, LAMA4, LAMB2, CD36, CD44, COL6A3, COL1A2, COL6A2, COL6A1, COL1A1", "1.94E − 07"], ["hsa04115: p53 signaling pathway", "17", "2.463768", "1.72E − 10", "STEAP3, CDK1, TP53, CHEK1, CDK6, SFN, PMAIP1, CDK4, CDK2, CCNB1, TP53I3, CCND1, CCNB2, RRM2, CASP8, SERPINE1, FAS", "2.16E − 07"], ["hsa05200: pathways in cancer", "32", "4.637681", "2.06E − 06", "WNT5A, STK36, ERBB2, MMP9, LPAR4, CXCL8, GLI2, TGFB1, TCF7L1, LAMB2, CXCR4, CASP8, FAS, MYC, BMP2, TGFBR1, TP53, ITGA2, BIRC5, CDK6, FZD2, CDK4, MECOM, COL4A6, CDK2, FZD6, LAMA2, SMO, LAMA1, LAMA4, CCND1, F2R", "2.58E − 03"], ["hsa05161: hepatitis B", "18", "2.608696", "3.02E − 06", "TGFBR1, MMP9, TP53, HSPG2, CXCL8, TLR3, BIRC5, CDK6, CDK4, CDK2, TGFB1, CCND1, CASP8, CREB3L4, FAS, MYC, CCNA2, NFATC1", "3.78E − 03"], [""], ["Downregulated", "hsa04723: retrograde endocannabinoid signaling", "38", "3.015873", "1.92E − 20", "ADCY1, GABRB3, GABRB2, GABRB1, ADCY5, RIMS1, KCNJ3, SLC32A1, PLCB4, CNR1, MGLL, GNG3, PLCB1, GNG7, GABRD, GABRG1, GABRG2, GABRA2, GABRA1, GABRA4, GABRA5, PRKCG, GRIA3, GRIA4, GRM1, ITPR1, PRKCB, SLC17A7, GRM5, SLC17A6, KCNJ6, KCNJ9, GRIA2, FAAH, GNB5, CACNA1D, CACNA1A, CACNA1B", "2.45E − 17"], ["hsa04724: glutamatergic synapse", "40", "3.174603", "2.94E − 20", "ADCY1, GRIK2, ADCY5, PPP3R1, GRIN3A, KCNJ3, SLC1A2, PLCB4, GRIN2C, SLC1A6, PPP3CB, DLG4, GNG3, PPP3CA, PLCB1, SLC1A1, GNG7, DLGAP1, GRIN2A, PRKCG, GRIA3, GRIA4, HOMER1, GRM1, SHANK2, SHANK3, ITPR1, PRKCB, GRM5, SLC17A7, GRM3, GRM2, SLC17A6, GRIA2, GRM7, GNB5, PLA2G4C, CACNA1D, GRK3, CACNA1A", "3.76E − 17"], ["hsa05032: morphine addiction", "32", "2.539683", "2.87E − 16", "ADCY1, GABRB3, GABRB2, ADCY5, GABRB1, GABBR1, GABBR2, ADORA1, KCNJ3, SLC32A1, PDE1C, PDE4A, PDE1A, GNG3, GNG7, GABRG1, GABRD, GABRG2, GABRA2, GABRA1, GABRA4, GABRA5, PRKCG, PDE10A, PRKCB, KCNJ6, PDE2A, KCNJ9, GNB5, GRK3, CACNA1A, CACNA1B", "4.22E − 13"], ["hsa04727: GABAergic synapse", "30", "2.380952", "2.91E − 15", "ADCY1, SLC6A1, GABRB3, GABRB2, ADCY5, GABRB1, GABBR1, GABBR2, SLC32A1, PLCL1, GAD2, GNG3, GAD1, NSF, GNG7, GABRG1, GABRD, GABRG2, GABARAPL1, GABRA2, GABRA1, GABRA4, GABRA5, PRKCG, PRKCB, KCNJ6, GNB5, CACNA1D, CACNA1A, CACNA1B", "3.69E − 12"], ["hsa04020: calcium signaling pathway", "43", "3.412698", "5.62E − 15", "SLC8A3, ADCY1, ERBB3, CAMK2G, PPP3R1, ITPKA, ATP2B2, ATP2B3, PLCB4, GRIN2C, PDE1C, PTK2B, PDE1A, PPP3CB, CAMK2B, PPP3CA, PLCB1, CAMK2A, NOS1, SLC8A2, CCKBR, CACNA1I, GRIN2A, PRKCG, GRM1, ITPR1, PRKCB, P2RX5, GRM5, GNAL, ADRB1, CAMK4, CHRM3, CHRM1, CACNA1G, RYR1, RYR2, CACNA1E, CACNA1D, HTR2C, CACNA1A, CACNA1B, HTR2A", "7.24E − 12"]], "row_count": 12, "column_count": 7, "numeric_cells": 59, "header_rows": 1, "locator": "section[4]/table-wrap[2]#tab3"}}, {"id": "asset:table:pmid:30405856:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:4668296199c594f3286ccb5c762fa4377544fa211faebdb8e42021fe4bdee699", "bytes": 2720, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[6]/table-wrap[1]#tab4", "version": null, "note": "The enriched pathways of top 4 modules from the protein-protein interaction network.", "structure": {"pmcid": "PMC6199874", "section_index": 6, "section_title": "2.4. Hub Genes and Module Screening from PPI Network", "row_count": 24, "column_count": 5}, "table": {"label": "Table 4", "caption": "The enriched pathways of top 4 modules from the protein-protein interaction network.", "rows": [["Module", "Term", "p value", "FDR", "Genes"], ["1", "Cell cycle", "7.17E − 13", "5.94E − 10", "CCNB1, CDK1, MAD2L1, CCNB2, BUB1, TTK, BUB1B, CHEK1, CDC20, MCM2, CCNA2"], ["Progesterone-mediated oocyte maturation", "4.89E − 06", "4.05E − 03", "CCNB1, CDK1, MAD2L1, CCNB2, BUB1, CCNA2"], ["p53 signaling pathway", "4.27E − 05", "3.54E − 02", "CCNB1, CDK1, CCNB2, RRM2, CHEK1"], ["Oocyte meiosis", "2.85E − 04", "0.235961", "CDK1, MAD2L1, BUB1, AURKA, CDC20"], ["DNA replication", "5.21E − 03", "4.233590", "POLE2, MCM2, RNASEH2A"], [""], ["2", "Neuroactive ligand-receptorinteraction", "4.44E − 11", "4.86E − 08", "OPRK1, GABBR1, NPY1R, GABBR2, ADORA1, S1PR3, GRM3, SSTR2, GRM2, GRM7, CNR1, S1PR5, ADRA2A"], ["Morphine addiction", "2.16E − 08", "2.36E − 05", "ADCY1, ADCY5, GABBR1, GNB5, GABBR2, GNG3, ADORA1, GNG7"], ["Glutamatergic synapse", "1.04E − 07", "1.14E − 04", "ADCY1, GRM3, GRM2, ADCY5, GRM7, GNB5, GNG3, GNG7"], ["GABAergic synapse", "4.26E − 07", "4.66E − 04", "ADCY1, ADCY5, GABBR1, GNB5, GABBR2, GNG3, GNG7"], ["cAMP signaling pathway", "4.42E − 06", "4.84E − 03", "ADCY1, SSTR2, NPY, ADCY5, GABBR1, GABBR2, NPY1R, ADORA1"], [""], ["3", "Calcium signaling pathway", "2.75E − 08", "2.95E − 05", "GRM5, PLCB4, CCKBR, CHRM3, CHRM1, PLCB1, GRM1, HTR2C, HTR2A, F2R"], ["Neuroactive ligand-receptorinteraction", "9.29E − 08", "9.95E − 05", "GRM5, CCKBR, CHRM3, CHRM1, F2RL1, LPAR4, NTSR2, GRM1, HTR2C, HTR2A, F2R"], ["Gap junction", "2.79E − 05", "2.99E − 02", "GRM5, PLCB4, PLCB1, GRM1, HTR2C, HTR2A"], ["Endocytosis", "7.19E − 05", "7.69E − 02", "SH3GL3, DNM3, DAB2, DNAJC6, DNM1, SH3GL2, F2R, AMPH"], ["Inflammatory mediator regulation of TRP channels", "6.88E − 04", "0.734597", "PLCB4, F2RL1, PLCB1, HTR2C, HTR2A"], [""], ["4", "Arrhythmogenic right ventricular cardiomyopathy (ARVC)", "3.06E − 12", "3.25E − 09", "CACNA2D1, CACNG8, CACNB2, RYR2, CACNG3, CACNB3, CACNG2, CACNB4, CACNA2D3, CACNA1D"], ["Cardiac muscle contraction", "5.12E − 12", "5.43E − 09", "CACNA2D1, CACNG8, CACNB2, RYR2, CACNG3, CACNB3, CACNG2, CACNB4, CACNA2D3, CACNA1D"], ["Hypertrophic cardiomyopathy (HCM)", "7.38E − 12", "7.82E − 09", "CACNA2D1, CACNG8, CACNB2, RYR2, CACNG3, CACNB3, CACNG2, CACNB4, CACNA2D3, CACNA1D"], ["Dilated cardiomyopathy", "1.47E − 11", "1.56E − 08", "CACNA2D1, CACNG8, CACNB2, RYR2, CACNG3, CACNB3, CACNG2, CACNB4, CACNA2D3, CACNA1D"], ["Oxytocin signaling pathway", "1.77E − 10", "1.88E − 07", "CACNA2D1, CCND1, CACNG8, CACNB2, RYR2, CACNG3, CACNB3, CACNG2, CACNB4, CACNA2D3, CACNA1D"]], "row_count": 24, "column_count": 5, "numeric_cells": 47, "header_rows": 1, "locator": "section[6]/table-wrap[1]#tab4"}}], "gaps": ["asset:data:geo:GSE66354 not downloaded", "asset:data:geo:GSE66354 licence not read"]}, "analysis": {"state": "partial", 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