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pmid:30719133
High Expression Levels of AGGF1 and MFAP4 Predict Primary Platinum-Based Chemoresistance and are Associated with Adverse Prognosis in Patients with Serous Ovarian Cancer.
Haiyue Zhao · Qian Sun · Lisong Li · Jinhua Zhou · Cong Zhang · Ting Hu · Xuemei Zhou · Long Zhang · Baiyu Wang · Bo Li · Tao Zhu · Hong Li
Journal of Cancer · 2019 doi:10.7150/jca.28127
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Complete file
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So we aimed to identify novel genes as predictors of primary platinum-based chemoresistance. Gene expression microarray analyses were performed to identify the genes related to primary platinum resistance in SOC on two discovery datasets (GSE51373, GSE63885) and one validation dataset (TCGA). Univariate and multivariate analyses with logistic regression were performed to evaluate the predictive values of the genes for platinum resistance. Machine learning algorithms (linear kernel support vector machine and artificial neural network) were applied to build prediction models. Univariate and multivariate analyses with Cox proportional hazards regression and log-rank tests were used to assess the effects of these gene signatures for platinum resistance on prognosis in two independent datasets (GSE9891, GSE32062). AGGF1 and MFAP4 were found highly expressed in patients with platinum-resistant SOC and independently predicted platinum resistance. Platinum resistance prediction models based on these targets had robust predictive power (highest AUC: 0.8056, 95% CI: 0.6338-0.9773; lowest AUC: 0.7245, 95% CI: 0.6052-0.8438). An AGGF1- and MFAP4-centered protein interaction network was built, and hypothetical regulatory pathways were identified. Enrichment analysis indicated that aberrations of extracellular matrix may play important roles in platinum resistance in SOC. High AGGF1 and MFAP4 expression levels were also related to shorter recurrence-free and overall survival in patients with SOC after adjustment for other clinical variables. Therefore, AGGF1 and MFAP4 are potential predictive biomarkers for response to platinum-based chemotherapy and survival outcomes in SOC.", "claims": [{"id": "claim-method", "statement": "Univariate analysis with Cox proportional hazards regression model was used to evaluate the correlations of AGGF1 and MFAP4 expression statuses with RFS and OS, and multivariate analysis with Cox proportional hazards regression model was applied to test the independent predictive ability of these two gene signatures for RFS and OS after adjusting for various clinical characteristics.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30719133", "locator": "sections[9] \"Survival analysis of AGGF1 and MFAP4\" paragraph 2", "quote": "Univariate analysis with Cox proportional hazards regression model was used to evaluate the correlations of AGGF1 and MFAP4 expression statuses with RFS and OS, and multivariate analysis with Cox proportional hazards regression model was applied to test the independent predictive ability of these two gene signatures for RFS and OS after adjusting for various clinical characteristics."}], "state": "complete"}, {"id": "claim-data-access", "statement": "GSE63885 and GSE51373 were defined as the discovery sets to explore gene signatures with high efficiency to distinguish platinum-resistant and platinum-sensitive patients, and TCGA SOC dataset (hereinafter inferred as TCGA) was analyzed as the validation dataset.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30719133", "locator": "sections[5] \"Screening and validation of platinum resistance-related genes\" paragraph 2", "quote": "GSE63885 and GSE51373 were defined as the discovery sets to explore gene signatures with high efficiency to distinguish platinum-resistant and platinum-sensitive patients, and TCGA SOC dataset (hereinafter inferred as TCGA) was analyzed as the validation dataset."}], "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:30719133"], "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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null, "group_sizes_basis": null, "platform": "570", "taxon": "Homo sapiens", "title": "Expression profile of 285 ovarian tumour samples", "resolution_checked_at": "2026-11-01T15:39:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "asset:table:pmid:30719133:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:a7b097219b57cc93c313e8c8e6f6aeba553ed8f0c1219811fc77f8ed29939cd7", "bytes": 896, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[3]/table-wrap[1]#T1", "version": null, "note": "General information of involved 3 datasets for developing gene signatures of predicting platinum resistance.", "structure": {"pmcid": "PMC6360311", "section_index": 3, "section_title": "Preparation of SOC datasets", "row_count": 17, "column_count": 4}, "table": {"label": "Table 1", "caption": "General information of involved 3 datasets for developing gene signatures of predicting platinum resistance.", "rows": [["Characteristic", "GSE63885", "GSE51373", "TCGA"], ["Platform", "HG-U133_Plus_2", "HG-U133_Plus_2", "HT_HG-U133A"], ["Total sample number", "101", "28", "578"], ["Enrolled samples*", "70", "28", "454"], ["Age", "", "", ""], ["median (range)", "/", "54 (47 - 79)", "58 (26 - 89)"], ["Chemotherapeutic response", "", ""], ["sensitive", "38", "18", "318"], ["resistance", "32", "10", "136"], ["Tumor grade", "", "", ""], ["1/2/3/4/unknown", "0/9/46/15/0", "high grade", "5/55/383/1/10"], ["Tumor stage", "", "", ""], ["I/II/III/IV/unknown", "0/2/59/9/0", "0/5/19/3/1", "13/21/350/68/2"], ["Debulking", "", "", ""], ["optimal", "14", "/", "301"], ["suboptimal", "56", "/", "111"], ["unknown", "0", "/", "42"]], "row_count": 17, "column_count": 4, "numeric_cells": 31, "header_rows": 1, "locator": "section[3]/table-wrap[1]#T1"}}, {"id": "asset:table:pmid:30719133:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:aca598dbcbf9fdfd1c7aeeff4d59036ed4e6e9d29a3f23fc884815fedb856b77", "bytes": 2203, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#T2", "version": null, "note": "Univariable and multivariable logistic regression models for platinum resistance in the discovery and validation datasets.", "structure": {"pmcid": "PMC6360311", "section_index": 12, "section_title": "AGGF and MFAP4 were independent predictors of primary platinum resistance", "row_count": 31, "column_count": 8}, "table": {"label": "Table 2", "caption": "Univariable and multivariable logistic regression models for platinum resistance in the discovery and validation datasets.", "rows": [["Datasets and clinical factors", "Univariate analysis", "Multivariate analysis"], ["OR", "95%CI", "p value", "OR", "95%CI", "p value"], ["GSE63885"], ["Tumor stage", "II", "1 (reference)", "1 (reference)"], ["III", "13205836.02", "0 - Inf", "0.99", "3537708.16", "0 - Inf", "0.99"], ["IV", "19564201.51", "0 - Inf", "0.99", "4665494.34", "0 - Inf", "0.99"], ["Tumor grade", "G2", "1 (reference)", "1 (reference)"], ["G3", "2.94", "0.55 - 15.7", "0.20", "1.87", "0.27 - 12.9", "0.52"], ["G4", "5.25", "0.8 - 34.43", "0.08", "3.05", "0.36 - 26.11", "0.30"], ["AGGF1", "high vs. low", "3.71", "1.33 - 10.32", "0.01", "3.32", "1.07 - 10.28", "0.03"], ["MFAP4", "high vs. low", "4.67", "1.69 - 12.9", "0.003", "3.64", "1.18 - 11.22", "0.02"], ["GSE51373"], ["Tumor stage", "II", "1 (reference)", "1 (reference)"], ["III", "2.33", "0.22 - 25.24", "0.48", "0.64", "0 - 139.25", "0.87"], ["IV", "8", "0.31 - 206.37", "0.21", "0.52", "0 - 279.37", "0.83"], ["Age", ">=60 vs. <60", "0.13", "0.01 - 1.22", "0.07", "0.11", "0 - 3.02", "0.19"], ["AGGF1", "high vs. low", "14.14", "1.46 - 137.3", "0.02", "18.51", "0.93 - 369.88", "0.05"], ["MFAP4", "high vs. low", "10.4", "1.62 - 66.9", "0.01", "15.22", "1.11 - 207.9", "0.04"], ["TCGA"], ["Tumor stage", "Ⅰ", "1 (reference)", "1 (reference)"], ["II", "0.28", "0.02 - 3.39", "0.31", "0", "0 - Inf", "0.98"], ["III", "2.39", "0.52 - 10.97", "0.26", "1.02", "0.2 - 5.06", "0.98"], ["IV", "3.2", "0.66 -15.61", "0.15", "1.64", "0.31 - 8.72", "0.56"], ["Tumor grade", "G1", "1 (reference)", "1 (reference)"], ["G2", "1.95", "0.2 - 18.7", "0.56", "1.5", "0.13 - 16.7", "0.74"], ["G3", "1.72", "0.19 - 15.52", "0.63", "1.15", "0.11 - 11.81", "0.90"], ["G4", "0", "0 - Inf", "0.98", "0", "0 - Inf", "0.99"], ["Age", ">=60 vs. <60", "1.08", "0.72 - 1.62", "0.71", "0.99", "0.62 - 1.59", "0.98"], ["Surgery", "Suboptimal vs. Optimal", "3.36", "2.13 - 5.3", "< 0.001", "3.16", "1.93 - 5.16", "< 0.001"], ["AGGF1", "high vs. low", "2.24", "1.47 - 3.41", "< 0.001", "2.54", "1.58 - 4.08", "< 0.001"], ["MFAP4", "high vs low", "1.81", "1.21 - 2.72", "0.004", "1.64", "1.03 - 2.62", "0.03"]], "row_count": 31, "column_count": 8, "numeric_cells": 142, "header_rows": 2, "locator": "section[12]/table-wrap[1]#T2"}}, {"id": "asset:table:pmid:30719133:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:9a0a38a3d4aacc11a61c3b4353cf879248d710a39fa274e7d85b103bff9d6aca", "bytes": 1787, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[19]/table-wrap[1]#T3A", "version": null, "note": "Univariate and multivariate Cox regression analysis for recurrence free survival in GSE9891 and GSE32062.", "structure": {"pmcid": "PMC6360311", "section_index": 19, "section_title": "(untitled)", "row_count": 22, "column_count": 8}, "table": {"label": "Table 3A", "caption": "Univariate and multivariate Cox regression analysis for recurrence free survival in GSE9891 and GSE32062.", "rows": [["Datasets and clinical factors", "Univariate analysis", "Multivariate analysis"], ["HR", "95%CI", "p value", "HR", "95%CI", "p value"], ["GSE9891"], ["Age", "≥60y vs. <60y", "1.282", "0.954 -1.724", "0.10", "1.479", "1.056 - 2.071", "0.023"], ["Tumor stage", "I", "1 (reference)", "1 (reference)"], ["II", "2.603", "0.477 - 14.22", "0.269", "2.972", "0.540 - 16.377", "0.211"], ["III", "9.774", "2.418 - 39.51", "0.001", "7.966", "1.941 - 32.692", "0.004"], ["IV", "14.809", "3.452 - 63.52", "2.86e-04", "10.498", "2.314 - 47.623", "0.002"], ["Tumor grade", "G1", "1 (reference)", "1 (reference)"], ["G2", "3.116", "1.252 - 7.755", "0.015", "1.711", "0.604 - 4.845", "0.312"], ["G3", "2.723", "1.109 - 6.684", "0.029", "1.406", "0.502 - 3.936", "0.517"], ["Surgery", "Suboptimal vs. optimal", "2.058", "1.489 - 2.844", "1.218e-05", "1.704", "1.203 - 2.413", "0.003"], ["AGGF1", "high vs. low", "1.532", "1.071 - 2.192", "0.020", "1.578", "1.069 - 2.330", "0.022"], ["MFAP4", "high vs. low", "1.708", "1.260 - 2.315", "5.595e-04", "1.418", "1.003 - 2.006", "0.048"], ["GSE32062"], ["Tumor stage", "III", "1 (reference)", "1 (reference)"], ["IV", "1.515", "1.088 - 2.109", "0.014", "1.327", "0.948 - 1.858", "0.099"], ["Tumor grade", "G2", "1 (reference)", "1 (reference)"], ["G3", "1.151", "0.868 - 1.527", "0.330", "1.121", "0.840 - 1.498", "0.438"], ["Surgery", "Suboptimal vs. optimal", "1.772", "1.315 - 2.387", "1.683e-04", "1.667", "1.234 - 2.250", "0.001"], ["AGGF1", "high vs. low", "1.777", "1.263 - 2.5", "9.666e-04", "1.757", "1.246 - 2.476", "0.001"], ["MFAP4", "high vs. low", "1.494", "1.096 - 2.037", "0.011", "1.417", "1.039 - 1.933", "0.028"]], "row_count": 22, "column_count": 8, "numeric_cells": 97, "header_rows": 2, "locator": "section[19]/table-wrap[1]#T3A"}}, {"id": "asset:table:pmid:30719133:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:5048cc7fb2cac3326bf45c3e6fab519008c6c02352a84624c9668981ac299533", "bytes": 1880, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[19]/table-wrap[2]#T3B", "version": null, "note": "Univariate and multivariate Cox regression analysis for overall survival in GSE9891 and GSE32062.", "structure": {"pmcid": "PMC6360311", "section_index": 19, "section_title": "(untitled)", "row_count": 22, "column_count": 8}, "table": {"label": "Table 3B", "caption": "Univariate and multivariate Cox regression analysis for overall survival in GSE9891 and GSE32062.", "rows": [["Datasets and clinical factors", "", "Univariate analysis", "Multivariate analysis"], ["", "HR", "95%CI", "p value", "HR", "95%CI", "p value"], ["GSE9891", "", "", "", "", "", "", ""], ["Age", "≥60y vs <60y", "1.458", "1.001 - 2.122", "0.049", "1.729", "1.125 - 2.655", "0.012"], ["Tumor stage", "I", "1 (reference)", "", "", "1 (reference)", "", ""], ["", "II", "0.483", "0.044 - 5.347", "0.553", "0.705", "0.062 - 7.947", "0.777"], ["", "III", "3.672", "0.903 - 14.935", "0.069", "3.103", "0.740 - 13.020", "0.122"], ["", "IV", "5.739", "1.301 - 25.319", "0.021", "4.929", "1.035 - 23.483", "0.045"], ["Tumor grade", "G1", "1 (reference)", "", "", "1 (reference)", "", ""], ["", "G2", "3.070", "0.937 - 10.06", "0.064", "1.343", "0.387 - 4.663", "0.642"], ["", "G3", "3.181", "0.999 - 10.13", "0.0502", "1.534", "0.453 - 5.192", "0.491"], ["Surgery", "Suboptimal vs optimal", "1.662", "1.117 - 2.471", "0.012", "1.309", "0.850 - 2.014", "0.221"], ["AGGF1", "high vs. low", "1.662", "1.081 - 2.555", "0.021", "2.014", "1.240 - 3.270", "0.005"], ["MFAP4", "high vs. low", "1.98", "1.33 - 2.947", "0.001", "1.660", "1.065 - 2.586", "0.025"], ["GSE32062", "", "", "", "", "", "", ""], ["Tumor stage", "III", "1 (reference)", "", "", "1 (reference)", "", ""], ["", "IV", "1.466", "0.981 - 2.189", "0.062", "1.323", "0.881 - 1.986", "0.177"], ["Tumor grade", "G2", "1 (reference)", "", "", "1 (reference)", "", ""], ["", "G3", "0.978", "0.684 - 1.399", "0.904", "0.926", "0.645 - 1.328", "0.675"], ["Surgery", "Suboptimal 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