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pmid:34434214
Ferroptosis-Related Genes in Lung Adenocarcinoma: Prognostic Signature and Immune, Drug Resistance, Mutation Analysis.
Ziyuan Ren · Minghui Hu · Zhonglin Wang · Junpeng Ge · Xiaoyan Zhou · Guoming Zhang · Hongying Zheng
Frontiers in genetics · 2021 doi:10.3389/fgene.2021.672904
Paper
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Experiment
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Data
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Analysis
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Execution
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Complete file
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However, the clinical significance of ferroptosis in lung adenocarcinoma (LUAD) remains elusive, and the potential targets for ferroptosis-based treatment are limited. In this study, we constructed a 15-gene prognostic signature predicting overall survival based on ferroptosis-related genes (ferroptosis driver genes VDAC2, GLS2, FLT3, TLR4, PHKG2, phosphogluconate dehydrogenase (PGD), PANX1, KRAS, PEBP1, ALOX15, and ALOX12B, and suppressor genes ACSL3, CISD1, FANCD2, and SLC3A2) in The Cancer Genome Atlas (TCGA)-LUAD cohort. The signature's predictive ability was validated in the GSE68465 and GSE72094 cohorts by survival analysis and independent prognostic analysis with clinical features. Nomograms were provided for clinical reference. Functional analysis revealed that ferroptosis was closely related to cell cycle, cell metabolism, and immune pathways. Pan-cancer analysis comprehensively analyzed these 15 genes in 33 cancer types, indicating that the heterogeneity of 15 genes was evident across different cancer types. Besides, these genes were critical regulators modulating drug resistance, tumor microenvironment infiltration, and cancer stemness. Then, we screened 10 genes (TLR4, PHKG2, PEBP1, GLS2, FLT3, ALOX15, ACSL3, CISD1, FANCD2, and SLC3A2) as potential targets for further research because their biological functions in ferroptosis were consistent with their prognostic significance. Somatic mutation and copy number variation analysis revealed that the alteration rates of KRAS, PGD, and ALOX15 were more than 1% and significantly associated with overall survival in LUAD. Moreover, the expression of KRAS and PGD was positively related to tumor mutation burden, indicating that KRAS and PGD could serve as novel biomarkers for predicting immunotherapy response rate. Our study identified and validated a ferroptosis-related gene signature for LUAD, provided a 10-gene set for future research, and screened KRAS and PGD as potential novel immunotherapy biomarkers.", "claims": [{"id": "claim-method", "statement": "Multivariate Cox regression of the 27 FRDEGs established a 15-gene signature. The risk score was calculated using the formula: Risk score = 0.063ACSL3 + 0.224ALOX12B-0.011 ALOX15 + 0.155CISD1 + 0.104FANCD2-0.308FLT3-0.569 GLS2 + 0.066KRAS + 0.118PANX1-0.358PEBP1 + 0.010PGD-0.251PHKG2 + 0.093SLC3A2-0.176TLR4 + 0.012VDAC2 {the gene symbol means the expression of the gene [log2(normalized gene expression + 1)]}.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34434214", "locator": "sections[12] \"Construction of the Prognostic Model\" paragraph 2", "quote": "Multivariate Cox regression of the 27 FRDEGs established a 15-gene signature. 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"GSM1855209", "GSM1855210", "GSM1855211", "GSM1855212", "GSM1855213", "GSM1855214", "GSM1855215", "GSM1855216", "GSM1855217", "GSM1855218", "GSM1855219", "GSM1855220", "GSM1855221", "GSM1855222", "GSM1855223", "GSM1855224", "GSM1855225", "GSM1855226", "GSM1855227", "GSM1855228", "GSM1855229", "GSM1855230", "GSM1855231", "GSM1855232", "GSM1855233", "GSM1855234", "GSM1855235", "GSM1855236", "GSM1855237", "GSM1855238"], "sample_count": 442, "group_sizes": null, "group_sizes_basis": null, "platform": "15048", "taxon": "Homo sapiens", "title": "KRAS mutation-associated gene expression, p53 and STK11 mutations, proliferation and immune surveillance in lung adenocarcinoma", "resolution_checked_at": "2026-11-01T15:39:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE68465 not downloaded", "asset:data:geo:GSE68465 licence not read", "asset:data:geo:GSE72094 not downloaded", "asset:data:geo:GSE72094 licence not read"]}, "analysis": {"state": "partial", "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": "Multivariate Cox regression of the 27 FRDEGs established a 15-gene signature. The risk score was calculated using the formula: Risk score = 0.063ACSL3 + 0.224ALOX12B-0.011 ALOX15 + 0.155CISD1 + 0.104FANCD2-0.308FLT3-0.569 GLS2 + 0.066KRAS + 0.118PANX1-0.358PEBP1 + 0.010PGD-0.251PHKG2 + 0.093SLC3A2-0.176TLR4 + 0.012VDAC2 {the gene symbol means the expression of the gene [log2(normalized gene expression + 1)]}."}}, {"id": "method-2", "family": "group_comparison", "specific": "anova", "label": "Group comparison", "dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 0.8, "band": "high", "quote": "analysis of variance"}}, {"id": "method-3", "family": "regression_modelling", "specific": "logistic", "label": "Regression modelling", "dsl_operations": ["glm_logit_fit"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["predictors_and_outcome"], "evidence": {"score": 0.8, "band": "high", "quote": "logistic regression"}}, {"id": "method-4", "family": "correlation_analysis", "specific": "pearson", "label": "Correlation analysis", "dsl_operations": ["pearson_r"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["paired_numeric_columns"], "evidence": {"score": 0.8, "band": "high", "quote": "Pearson correlation"}}, {"id": "method-5", "family": "correlation_analysis", "specific": "spearman", "label": "Correlation analysis", "dsl_operations": ["spearman_rho"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["paired_numeric_columns"], "evidence": {"score": 0.8, "band": "high", "quote": "Spearman correlation"}}, {"id": "method-6", "family": "contingency_analysis", "specific": "chi_square", "label": "Categorical (contingency table) analysis", "dsl_operations": ["chi_square_test"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["categorical_cross_tabulation"], "evidence": {"score": 0.8, "band": "high", "quote": "Chi-square"}}, {"id": "method-7", "family": "multi_omics_integration", "specific": "pathway_progeny", "label": "Multi-omics integration", "dsl_operations": ["multiomics_factor_analysis", "joint_pathway_score"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["aligned_multi_layer_matrices"], "evidence": {"score": 0.8, "band": "high", "quote": "progeny"}}], "targets": [], "gaps": ["method.reader_differs_from_extractor"]}, "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", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["cox_ph"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: cox_proportional_hazards."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE68465", "GSE72094"], "resolved_accessions": ["GSE68465", "GSE72094"], "statements": ["The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author."], "basis": "The paper names GSE68465, GSE72094 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:34434214", "data:geo:GSE68465"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE68465"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:34:19Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 61058, "completion_tokens": 3568, "cached_tokens": 776}}, "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:34434214", "type": "paper", "label": "pmid:34434214"}, {"id": "source:pmid:34434214", "type": "manuscript", "label": "PMID 34434214 full text"}, {"id": "data:geo:GSE68465", "type": "dataset", "label": "GEO GSE68465"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:34434214", "type": "paper", "label": "pmid:34434214"}, {"id": "source:pmid:34434214", "type": "manuscript", "label": "PMID 34434214 full text"}, {"id": "data:geo:GSE68465", "type": "dataset", "label": "GEO GSE68465"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-34434214", "type": "extraction", "used": ["source:pmid:34434214"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE68465", "type": "accession_resolution", "used": ["data:geo:GSE68465"], "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:34434214", "parent_hash": "sha256:2a76d2bc171889d65600fe0e938d2a1d334dfdd48168bda8c50d62a1888b34bb", "fork_of": null, "generation": 6}, "gaps": ["asset:data:geo:GSE68465 licence not read", "asset:data:geo:GSE68465 not downloaded", "asset:data:geo:GSE72094 licence not read", "asset:data:geo:GSE72094 not downloaded", "execution.not_run", "method.reader_differs_from_extractor", "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": ["Multivariate Cox regression of the 27 FRDEGs established a 15-gene signature. The risk score was calculated using the formula: Risk score = 0.063ACSL3 + 0.224ALOX12B-0.011 ALOX15 + 0.155CISD1 + 0.104FANCD2-0.308FLT3-0.569 GLS2 + 0.066KRAS + 0.118PANX1-0.358PEBP1 + 0.010PGD-0.251PHKG2 + 0.093SLC3A2-0.176TLR4 + 0.012VDAC2 {the gene symbol means the expression of the gene [log2(normalized gene expression + 1)]}."], "order_basis": "analysis_only", "id": "assay:1"}]}