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pmid:31086582
A prognostic prediction system for hepatocellular carcinoma based on gene co-expression network.
Lianyue Guan · Qiang Luo · Na Liang · Hongyu Liu
Experimental and therapeutic medicine · 2019 doi:10.3892/etm.2019.7494
Paper
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Experiment
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Data
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Analysis
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Complete file
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Gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The overlapping differentially expressed genes (DEGs) between these two datasets were identified using the limma package in R. Prognostic genes were further identified by Cox regression using the survival package. The significantly co-expressed gene pairs were selected using the R function cor to construct the co-expression network. Functional and module analyses were also performed. Next, a prognostic prediction system was established by Bayes discriminant analysis using the discriminant.bayes function in the e1071 package, which was further validated in another independent GEO dataset. A total of 177 overlapping DEGs were identified from TCGA and the GEO dataset (GSE36376). Furthermore, 161 prognostic genes were selected and the top six were stanniocalcin 2, carbonic anhydrase 12, cell division cycle (CDC) 20, deoxyribonuclease 1 like 3, glucosylceramidase β3 and metallothionein 1G. A gene co-expression network involving 41 upregulated and 52 downregulated genes was constructed. SPC24, endothelial cell specific molecule 1, CDC20, CDCA3, cyclin (CCN) E1 and chromatin licensing and DNA replication factor 1 were significantly associated with cell division, mitotic cell cycle and positive regulation of cell proliferation. CCNB1, CCNE1, CCNB2 and stratifin were clearly associated with the p53 signaling pathway. A prognostic prediction system containing 55 signature genes was established and then validated in the GEO dataset GSE20140. In conclusion, the present study identified a number of prognostic genes and established a prediction system to assess the prognosis of HCC patients.", "claims": [{"id": "claim-method", "statement": "These data were used to screen prognostic genes from the overlapping DEGs using Cox regression (26) from the survival package of R.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:31086582", "locator": "sections[6] \"Screening of prognostic genes\" paragraph 2", "quote": "These data were used to screen prognostic genes from the overlapping DEGs using Cox regression (26) from the survival package of R."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:31086582", "locator": "sections[21] \"Availability of data and materials\" paragraph 2", "quote": "The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:31086582"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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Downregulated genes"], [""], ["Gene", "logFC", "P-value", "FDR"], [""], ["CYP4A22", "−0.492", "2.25×10−12", "8.69×10−11"], ["TMEM82", "−0.519", "5.69×10−13", "2.36×10−11"], ["GLYAT", "−0.536", "1.39×10−16", "7.57×10−15"], ["GBA3", "−0.546", "1.40×10−15", "7.17×10−14"], ["APOF", "−0.555", "1.52×10−18", "1.00×10−16"], ["SLC22A1", "−0.565", "1.50×10−20", "1.23×10−18"], ["DNASE1L3", "−0.580", "4.07×10−17", "2.31×10−15"], ["ECM1", "−0.591", "7.68×10−17", "4.26×10−15"], ["CETP", "−0.602", "1.68×10−15", "8.57×10−14"], ["GLS2", "−0.603", "6.99×10−20", "5.35×10−18"], ["GREM2", "−0.614", "1.99×10−16", "1.06×10−14"], ["AADAT", "−0.615", "2.46×10−17", "1.42×10−15"], ["MME", "−0.616", "6.41×10−17", "3.57×10−15"], ["SRD5A2", "−0.650", "5.30×10−19", "3.64×10−17"], ["C9", "−0.655", "7.70×10−28", "1.33×10−25"], ["CLRN3", "−0.701", "2.09×10−20", "1.68×10−18"], ["IGFALS", "−0.716", "7.36×10−26", "1.03×10−23"], ["TMEM27", "−0.730", "5.13×10−21", "4.37×10−19"], ["ASPG", "−0.735", "1.68×10−25", "2.26×10−23"], ["SRPX", "−0.763", "7.97×10−21", "6.69×10−19"], ["MYOM2", "−0.784", "3.33×10−18", "2.13×10−16"], ["MT1F", "−0.846", "1.21×10−34", "5.04×10−32"], ["PTH1R", "−0.866", "3.18×10−28", "5.82×10−26"], ["FCN3", "−0.978", "1.24×10−42", "9.37×10−40"], ["HAMP", "−1.052", "2.53×10−55", "2.78×10−52"], ["MT1H", "−1.425", "5.74×10−76", "6.94×10−72"]], "row_count": 63, "column_count": 4, "numeric_cells": 180, "header_rows": 3, "locator": "section[16]/table-wrap[1]#tIII-etm-0-0-7494"}}, {"id": "asset:table:pmid:31086582:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:32512e0e521abcb5d8c8f600dcd03b8da118e489802be4d691ca08204b05f087", "bytes": 2717, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[15]/table-wrap[1]#tI-etm-0-0-7494", "version": null, "note": "GO functional terms enriched by the prognostic genes in the co-expression network.", "structure": {"pmcid": "PMC6489019", "section_index": 15, "section_title": "Gene co-expression network", "row_count": 22, "column_count": 4}, "table": {"label": "Table I.", "caption": "GO functional terms enriched by the prognostic genes in the co-expression network.", "rows": [["Category/term", "Count", "P-value", "Genes"], ["Biological process"], ["GO:0051301~cell division", "19", "2.29×10−13", "CDC7, KIFC1, NEK2, AURKA, CDC20, PTTG1, CDC25A, SPC24, FAM83D, CCNB1, CCNE1, CDCA8, CCNB2, NCAPG, BUB1, CENPW, CDCA5, CCNA2, CDCA3"], ["GO:0007067~mitotic nuclear division", "16", "2.760×10−12", "NEK2, CDC20, AURKA, PBK, AURKB, CEP55, PTTG1, CDC25A, SPC24, FAM83D, CCNB2, BUB1, CENPW, CDCA5, CCNA2, CDCA3"], ["GO:0000082~G1/S transition of mitotic cell cycle", "8", "1.05×10−6", "CDC7, CCNE1, CDC45, POLE2, CDKN3, CDCA5, CDC25A, CDT1"], ["GO:0007062~sister chromatid cohesion", "7", "1.66×10−5", "SPC24, CDCA8, CENPL, BUB1, CDC20, AURKB, CDCA5"], ["GO:0006260~DNA replication", "7", "1.63×10−4", "CDC7, CDC45, POLE2, CHAF1B, CDC25A, DSCC1, CDT1"], ["GO:0008284~positive regulation of cell proliferation", "7", "3.56×10−2", "CDC7, PRC1, PTH1R, PDGFRA, CDC20, ESM1, VIPR1"], ["GO:0071276~cellular response to cadmium ion", "6", "2.07×10−8", "MT1A, CYP1A2, MT1H, MT1X, MT1G, MT1F"], ["GO:0000086~G2/M transition of mitotic cell cycle", "6", "7.65×10−4", "CCNB1, CCNB2, NEK2, AURKA, CDC25A, HMMR"], ["GO:0006281~DNA repair", "6", "7.87×10−3", "RAD51AP1, POLE2, PTTG1, CHAF1B, UBE2T, RAD51"], ["GO:0008283~cell proliferation Cellular component", "6", "4.32×10−2", "FAM83D, STIL, DLGAP5, BUB1, AURKB, CDC25A"], ["GO:0005654~nucleoplasm", "26", "1.40×10−3", "PRC1, AURKA, AURKB, CDT1, CCNE1, CDC45, CDCA8, POLE2, BUB1, THRSP, CCNA2, CDCA5, TOP2A, CDC7, RAD51AP1, CENPL, CDC20, CDC25A, RAD51, CCNB1, CCNB2, CENPW, CHAF1B, UBE2T, DSCC1, KIF20A"], ["GO:0005576~extracellular region", "14", "4.86×10−2", "C7, CNDP1, HSD17B13, COL15A1, CCL19, DCN, ESM1, ECM1, GREM2, DNASE1L3, MMP11, LPA, APOF, MFAP4"], ["GO:0005813~centrosome", "9", "1.13×10−3", "CCNB1, STIL, CDC45, CCNB2, NCAPG, NEK2, AURKA, CDC20, CEP55"], ["GO:0048471~perinuclear region of cytoplasm", "9", "1.09×10−2", "MT1A, AURKA, CDC20, CDKN3, MT1H, MT1X, MT1G, RAD51, MT1F"], ["GO:0030496~midbody", "8", "3.22×10−6", "CDCA8, PRC1, NEK2, AURKA, CEP55, AURKB, ECT2, KIF20A"], ["GO:0005819~spindle", "6", "3.16×10−4", "KIFC1, PRC1, AURKA, CDC20, AURKB, KIF20A"], ["Molecular function"], ["GO:0019901~protein kinase binding", "9", "7.10×10−4", "CCNB1, FAM83D, CCNE1, PRC1, AURKA, SFN, CCNA2, CDC25A, KIF20A"], ["GO:0004672~protein kinase activity", "7", "1.06×10−2", "CDC7, NEK2, PDGFRA, BUB1, AURKA, PBK, AURKB"], ["GO:0004674~protein serine/threonine kinase activity", "6", "4.48×10−2", "CDC7, NEK2, BUB1, AURKA, PBK, AURKB"]], "row_count": 22, "column_count": 4, "numeric_cells": 73, "header_rows": 1, "locator": "section[15]/table-wrap[1]#tI-etm-0-0-7494"}}, {"id": "asset:table:pmid:31086582:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:710f5922ba04d53987646b4efd73b9f9081b4e74f6e924c788079a77c6e5e8cf", "bytes": 875, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[15]/table-wrap[2]#tII-etm-0-0-7494", "version": null, "note": "Significantly enriched pathways for the prognostic genes in the co-expression network.", "structure": {"pmcid": "PMC6489019", "section_index": 15, "section_title": "Gene co-expression network", "row_count": 8, "column_count": 4}, "table": {"label": "Table II.", "caption": "Significantly enriched pathways for the prognostic genes in the co-expression network.", "rows": [["Term", "Count", "P-value", "Genes"], ["hsa04110:Cell cycle", "11", "4.51×10−9", "CCNB1, CDC7, CCNE1, CDC45, CCNB2, BUB1, CDC20, PTTG1, SFN, CCNA2, CDC25A"], ["hsa04978:Mineral absorption", "5", "2.10×10−4", "MT1A, MT1H, MT1X, MT1G, MT1F"], ["hsa04115:p53 signaling pathway", "4", "9.25×10−3", "CCNB1, CCNE1, CCNB2, SFN"], ["hsa00380:Tryptophan metabolism", "3", "2.77×10−2", "AADAT, CYP1A2, INMT"], ["hsa00232:Caffeine metabolism", "2", "3.22×10−2", "NAT2, CYP1A2"], ["hsa00140:Steroid hormone biosynthesis", "3", "3.45×10−2", "CYP3A4, SRD5A2, CYP1A2"], ["hsa05204:Chemical carcinogenesis", "3", "4.53×10−2", "CYP3A4, NAT2, CYP1A2"]], "row_count": 8, "column_count": 4, "numeric_cells": 22, "header_rows": 1, "locator": "section[15]/table-wrap[2]#tII-etm-0-0-7494"}}, {"id": "asset:table:pmid:31086582:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:ee1449538557ef9d0579215cf2937fa27e8c97be65c0799bdf72d501cf6b477a", "bytes": 3190, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#tIII-etm-0-0-7494", "version": null, "note": "The 55 signature genes involved in the prognostic prediction system.", "structure": {"pmcid": "PMC6489019", "section_index": 16, "section_title": "Prognostic prediction system", "row_count": 63, "column_count": 4}, "table": {"label": "Table III.", "caption": "The 55 signature genes involved in the prognostic prediction system.", "rows": [["A, Upregulated genes"], [""], ["Gene", "logFC", "P-value", "FDR"], ["SPC24", "1.777", "8.57×10−33", "2.66×10−30"], ["TGM3", "1.396", "4.38×10−35", "1.96×10−32"], ["KIF20A", "1.173", "2.42×10−30", "5.74×10−28"], ["ESM1", "1.162", "6.50×10−30", "1.40×10−27"], ["CDC20", "1.106", "1.51×10−30", "3.88×10−28"], ["CDCA3", "1.018", "3.84×10−23", "4.22×10−21"], ["CCNE1", "0.964", "4.97×10−19", "3.47×10−17"], ["TNFRSF4", "0.949", "8.28×10−19", "5.59×10−17"], ["COL15A1", "0.942", "2.28×10−25", "3.00×10−23"], ["CELSR3", "0.921", "1.59×10−19", "1.16×10−17"], ["CEP55", "0.920", "1.99×10−17", "1.19×10−15"], ["CDT1", "0.860", "4.43×10−20", "3.41×10−18"], ["C16orf59", "0.846", "1.13×10−16", "6.18×10−15"], ["MUC13", "0.800", "1.07×10−19", "7.93×10−18"], ["GPC3", "0.778", "9.91×10−26", "1.36×10−23"], ["MMP11", "0.723", "2.34×10−16", "1.24×10−14"], ["IGF2BP3", "0.702", "2.73×10−12", "1.04×10−10"], ["STC2", "0.687", "1.29×10−13", "5.67×10−12"], ["RAD51AP1", "0.672", "3.06×10−11", "1.05×10−9"], ["CCNB1", "0.653", "1.50×10−14", "7.08×10−13"], ["STIL", "0.622", "1.95×10−10", "6.11×10−9"], ["CA12", "0.615", "9.69×10−11", "3.15×10−9"], ["PNMA3", "0.550", "8.68×10−7", "1.55×10−5"], ["POLE2", "0.540", "4.99×10−8", "1.07×10−6"], ["FOXD2", "0.534", "3.59×10−7", "6.83×10−6"], ["MSX1", "0.531", "4.53×10−7", "8.45×10−6"], ["ITPKA", "0.525", "1.77×10−8", "4.16×10−7"], ["ACTG2", "0.525", "3.01×10−8", "6.78×10−7"], ["AKR1B10", "0.514", "7.73×10−13", "3.14×10−11"], [""], ["B, Downregulated genes"], [""], ["Gene", "logFC", "P-value", "FDR"], [""], ["CYP4A22", "−0.492", "2.25×10−12", "8.69×10−11"], ["TMEM82", "−0.519", "5.69×10−13", "2.36×10−11"], ["GLYAT", "−0.536", "1.39×10−16", "7.57×10−15"], ["GBA3", "−0.546", "1.40×10−15", "7.17×10−14"], ["APOF", "−0.555", "1.52×10−18", "1.00×10−16"], ["SLC22A1", "−0.565", "1.50×10−20", "1.23×10−18"], ["DNASE1L3", "−0.580", "4.07×10−17", "2.31×10−15"], ["ECM1", "−0.591", "7.68×10−17", "4.26×10−15"], ["CETP", "−0.602", "1.68×10−15", "8.57×10−14"], ["GLS2", "−0.603", "6.99×10−20", "5.35×10−18"], ["GREM2", "−0.614", "1.99×10−16", "1.06×10−14"], ["AADAT", "−0.615", "2.46×10−17", "1.42×10−15"], ["MME", "−0.616", "6.41×10−17", "3.57×10−15"], ["SRD5A2", "−0.650", "5.30×10−19", "3.64×10−17"], ["C9", "−0.655", "7.70×10−28", "1.33×10−25"], ["CLRN3", "−0.701", "2.09×10−20", "1.68×10−18"], ["IGFALS", "−0.716", "7.36×10−26", "1.03×10−23"], ["TMEM27", "−0.730", "5.13×10−21", "4.37×10−19"], ["ASPG", "−0.735", "1.68×10−25", "2.26×10−23"], ["SRPX", "−0.763", "7.97×10−21", "6.69×10−19"], ["MYOM2", "−0.784", "3.33×10−18", "2.13×10−16"], ["MT1F", "−0.846", "1.21×10−34", "5.04×10−32"], ["PTH1R", "−0.866", "3.18×10−28", "5.82×10−26"], ["FCN3", "−0.978", "1.24×10−42", "9.37×10−40"], ["HAMP", 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