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pmid:31794632
Genome-wide screening of abberant methylated drivers combined with relative risk loci in bladder cancer.
Chuanjie Zhang · Kangjie Shen · Yuxiao Zheng · Feng Qi · Jun Luo
Cancer medicine · 2020 doi:10.1002/cam4.2665
Paper
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Experiment
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Data
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Complete file
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MethylMix package was used for identifying methylation-driven genes and functional analysis was mainly performed based on ConsensusPathDB database. Then, Cox regression method was utilized to find prognostic MDGs, and we selected 17 hub genes via stepwise regression and multivariate Cox models. Kruskal-Wallis test was implemented for comparisons between risk with other clinical variables. Moreover, we constructed the risk model and validated it in GSE13507. Gene set enrichment analysis was performed using the levels of risk score as the phenotype. Additionally, we further screened out the relative methylation sites associated with the 17 hub genes. Cox regression and Survival analysis were conducted to find the specifically prognostic sites.\nRESULTS: Two hundred and twenty-eight MDGs were chosen by ConsensusPathDB database. Results revealed that most conspicuous pathways were transcriptional mis-regulation pathways in cancer and EMT. After Cox regression analysis, 17 hub epigenetic MDGs were identified. We calculated the risk score and found satisfactory predictive efficiency by ROC curve (AUC = 0.762). In the validation group from GSE13507, 17 hub genes remained higher predictive value with AUC = 0.723 and patients in high-risk group. Meanwhile, Kruskal-Wallis test revealed that higher risk score correlated with a higher level of TNM stage, tumor grade, and advanced pathological stages. Then, identified 38 risk methylated loci that highly associated with prognosis. Last, gene set enrichment analysis revealed that high-risk level of MDGs may correlate with several important pathways, including MAPK signaling pathway and so on.\nCONCLUSION: Our study indicated several hub-MDGs, calculated novel risk score and explored the prognostic value in BCa, which provided a promising approach to BCA prognosis assessment.", "claims": [{"id": "claim-method", "statement": "We conducted the univariate Cox regression analysis to select prognostic MDGs with P < .05 as the threshold.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:31794632", "locator": "sections[5] \"Construction and evaluation of epigenetic risk score based on MDGs\" paragraph 2", "quote": "We conducted the univariate Cox regression analysis to select prognostic MDGs with P < .05 as the threshold."}], "state": "complete"}, {"id": "claim-data-access", "statement": "We obtained RNA‐seq data of transcriptome profiles of BCA from TCGA database (https://portal.gdc.cancer.gov/), including 414 tumor tissues and 10 normal tissues. 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ConsensusPathDB database", "structure": {"pmcid": "PMC6970050", "section_index": 13, "section_title": "Functional enriched pathways", "row_count": 41, "column_count": 3}, "table": {"label": "Table 2", "caption": "Functional analysis of MDGs based on ConsensusPathDB database", "rows": [["Enriched pathway", "P value", "source"], ["Signaling mediated by p38‐alpha and p38‐beta", ".024851855", "PID"], ["Wnt‐beta‐catenin Signaling Pathway in Leukemia", ".01023165", "Wikipathways"], ["WNT‐Core", ".037948147", "Signalink"], ["Glutathione metabolism", ".00704807", "KEGG"], ["Signaling events mediated by HDAC Class III", ".030398536", "PID"], ["B Cell Receptor Signaling Pathway", ".031370148", "Wikipathways"], ["Fas Ligand pathway and Stress induction of Heat Shock Proteins regulation", ".036385809", "Wikipathways"], ["Transcriptional cascade regulating adipogenesis", ".003598992", "Wikipathways"], ["Hydroxycarboxylic acid‐binding receptors", ".000144888", "Reactome"], ["Transcriptional misregulation in cancer", ".040866181", "KEGG"], ["Chemokine receptors bind chemokines", ".047839785", "Reactome"], ["FTO Obesity Variant Mechanism", ".001321732", "Wikipathways"], ["White fat cell differentiation", ".001423078", "Wikipathways"], ["Epithelial to mesenchymal transition in colorectal cancer", ".025906124", "Wikipathways"], ["TYROBP Causal Network", ".008528042", "Wikipathways"], ["Bopindolol Action Pathway", ".008924337", "SMPDB"], ["Timolol Action Pathway", ".008924337", "SMPDB"], ["Carteolol Action Pathway", ".008924337", "SMPDB"], ["Bevantolol Action Pathway", ".008924337", "SMPDB"], ["Practolol Action Pathway", ".008924337", "SMPDB"], ["Dobutamine Action Pathway", ".008924337", "SMPDB"], ["Isoprenaline Action Pathway", ".008924337", "SMPDB"], ["Arbutamine Action Pathway", ".008924337", "SMPDB"], ["Levobunolol Action Pathway", ".008924337", "SMPDB"], ["Metipranolol Action Pathway", ".008924337", "SMPDB"], ["Sotalol Action Pathway", ".008924337", "SMPDB"], ["Epinephrine Action Pathway", ".008924337", "SMPDB"], ["Betaxolol Action Pathway", ".008924337", "SMPDB"], ["Atenolol Action Pathway", ".008924337", "SMPDB"], ["Alprenolol Action Pathway", ".008924337", "SMPDB"], ["Acebutolol Action Pathway", ".008924337", "SMPDB"], ["Propranolol Action Pathway", ".008924337", "SMPDB"], ["Pindolol Action Pathway", ".008924337", "SMPDB"], ["Penbutolol Action Pathway", ".008924337", "SMPDB"], ["Oxprenolol Action Pathway", ".008924337", "SMPDB"], ["Metoprolol Action Pathway", ".008924337", "SMPDB"], ["Esmolol Action Pathway", ".008924337", "SMPDB"], ["Bisoprolol Action Pathway", ".008924337", "SMPDB"], ["Bupranolol Action Pathway", ".008924337", "SMPDB"], ["Nebivolol Action Pathway", ".008924337", "SMPDB"]], "row_count": 41, "column_count": 3, "numeric_cells": 41, "header_rows": 1, "locator": "section[13]/table-wrap[1]#cam42665-tbl-0002"}}, {"id": "asset:table:pmid:31794632:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:f55c5052933b987f5f9d6a84d6bb8897639e650de05748e2535b833d8a1da6bf", "bytes": 2752, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#cam42665-tbl-0003", "version": null, "note": "Screening of 38 prognostic risk loci associated with hub MDGs in Bca", "structure": {"pmcid": "PMC6970050", "section_index": 16, "section_title": "Screening of risk methylation loci with survival analysis, joint survival analysis", "row_count": 39, "column_count": 5}, "table": {"label": "Table 3", "caption": "Screening of 38 prognostic risk loci associated with hub MDGs in Bca", "rows": [["Risk methtylated locus", "Related genes", "Hazard ratio", "z", "P value"], ["cg18414381", "EHF", "3.9737182", "3.347493733", ".000815458"], ["cg05503887", "EHF", "3.296494314", "3.334039828", ".000855944"], ["cg00543460", "TPM1", "0.313566503", "−3.040593266", ".002361126"], ["cg11065015", "NRSN2", "0.171047292", "−3.031903254", ".002430171"], ["cg13836318", "TPM1", "0.000319606", "−3.014958919", ".002570141"], ["cg24504361", "KRT8", "6.742218982", "2.907971041", ".00363782"], ["cg14506696", "DAPP1", "3.366923308", "2.895197969", ".003789195"], ["cg21614638", "DAPP1", "2.982090283", "2.81620796", ".00485942"], ["cg24097814", "KRT8", "3.116236706", "2.791702503", ".005243154"], ["cg08198488", "TPM1", "0.293122612", "−2.782702312", ".005390824"], ["cg10397389", "DAPP1", "2.804089164", "2.770618241", ".005594998"], ["cg01902605", "BHMT2", "0.156581583", "−2.672356579", ".007532056"], ["cg12494355", "TPM2", "0.095012775", "−2.660337122", ".007806247"], ["cg10843343", "KRT8", "5.522987956", "2.648437613", ".008086477"], ["cg22235258", "EHF", "2.970907821", "2.633435641", ".008452585"], ["cg00520135", "TPM1", "0.199663869", "−2.632332676", ".008480078"], ["cg19460095", "EHF", "2.88706523", "2.62182459", ".008746043"], ["cg17147440", "TPM1", "0.38112838", "−2.608256727", ".009100467"], ["cg26357344", "KRT8", "2.626134721", "2.58341772", ".00978268"], ["cg13107144", "TPM1", "0.080325594", "−2.567638984", ".010239373"], ["cg06398236", "DAPP1", "3.783262029", "2.507009355", ".012175749"], ["cg06997997", "MFAP4", "0.058274726", "−2.502867154", ".012319178"], ["cg03790745", "RCOR2", "0.002665687", "−2.480754698", ".013110456"], ["cg07814567", "DAPP1", "2.30196051", "2.478978727", ".013175916"], ["cg10403394", "TPM1", "0.231823345", "−2.390524206", ".01682434"], ["cg21083175", "RCOR2", "0.188494833", "−2.368506257", ".017860078"], ["cg03400060", "BHMT2", "0.228984691", "−2.360536791", ".018248508"], ["cg14260530", "AKNA", "0.162252883", "−2.333684214", ".019612263"], ["cg18560551", "EHF", "2.009472208", "2.329803583", ".019816535"], ["cg21867345", "ZKSCAN7", "2.078224581", "2.182145936", ".029098764"], ["cg13969788", "TPM2", "0.400926556", "−2.158779228", ".030867299"], ["cg14022090", "EHF", "2.242798579", "2.148000039", ".031713752"], ["cg08162426", "CPNE8", "2.345731899", "2.132073638", ".033000793"], ["cg22619810", "RCOR2", "0.015622716", "−2.130825555", ".033103516"], ["cg20324165", "KRT8", "2.762704434", "2.109031651", ".03494185"], ["cg13999433", "AKNA", "0.137520251", "−2.017220181", ".043672541"], ["cg02619205", "AKNA", "0.36559657", "−1.976424603", ".048106707"], ["cg01835489", "KRT8", "2.264564818", "1.964142113", ".049513614"]], "row_count": 39, "column_count": 5, "numeric_cells": 152, "header_rows": 1, "locator": "section[16]/table-wrap[1]#cam42665-tbl-0003"}}], "gaps": ["asset:data:geo:GSE13507 not downloaded", "asset:data:geo:GSE13507 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "survival_analysis", "specific": "cox_proportional_hazards", "label": "Survival analysis", "dsl_operations": ["cox_ph"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "We conducted the univariate Cox regression analysis to select prognostic MDGs with P < .05 as the threshold."}}, {"id": "method-2", "family": "diagnostic_evaluation", "specific": "roc", "label": "Diagnostic test evaluation", "dsl_operations": ["confusion_counts", "roc_curve", "sensitivity_specificity", "solve_confusion_matrix", "classification_metrics", "published_precision_envelope"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["reference_standard_and_test"], "evidence": {"score": 0.7, "band": "medium", "quote": "ROC curve"}}], "targets": [], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", 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The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE13507"], "resolved_accessions": ["GSE13507"], "statements": ["We obtained RNA‐seq data of transcriptome profiles of BCA from TCGA database (https://portal.gdc.cancer.gov/), including 414 tumor tissues and 10 normal tissues. We used edgeR package19 to normalize the raw data. Moreover, we utilized the tool of TCGA‐Assembler to download the DNA methylation data (419 BCA and corresponding 21 normal samples) based on the Illumina Infinium Human Methylation 450 platform, which detecting over 480 K human genome methylated sites. Limma package was applied to do the normalization.20"], "basis": "The paper names GSE13507 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["cox_ph"], "assets": ["source:pmid:31794632", "data:geo:GSE13507", "asset:table:pmid:31794632:1", "asset:table:pmid:31794632:2", "asset:table:pmid:31794632:3"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE13507"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:17:16Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": null}, "calls": 3, "usage": {"prompt_tokens": 21626, "completion_tokens": 3201, "cached_tokens": 784}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:31794632", "type": "paper", "label": "pmid:31794632"}, {"id": "source:pmid:31794632", "type": "manuscript", "label": "PMID 31794632 full text"}, {"id": "data:geo:GSE13507", "type": "dataset", "label": "GEO GSE13507"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:31794632", "type": "paper", "label": "pmid:31794632"}, {"id": "source:pmid:31794632", "type": "manuscript", "label": "PMID 31794632 full text"}, {"id": "data:geo:GSE13507", "type": "dataset", "label": "GEO GSE13507"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-31794632", "type": "extraction", "used": ["source:pmid:31794632"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE13507", "type": "accession_resolution", "used": ["data:geo:GSE13507"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:31794632", "parent_hash": "sha256:73b6700beca5f77826242a9a270fbd6bb68d618ed15518faa7021d4389ded41f", "fork_of": null, "generation": 7}, "gaps": ["asset:data:geo:GSE13507 licence not read", "asset:data:geo:GSE13507 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["We conducted the univariate Cox regression analysis to select prognostic MDGs with P < .05 as the threshold."], "order_basis": "analysis_only", "id": "assay:1"}]}