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pmid:34422970
Prognostic and immune implications of a novel ferroptosis-related ten-gene signature in lung adenocarcinoma.
Chao Ma · Feng Li · Huan Luo
Annals of translational medicine · 2021 doi:10.21037/atm-20-7936
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Complete file
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Ferroptosis, a novel iron-dependent form of regulated cell death, can be induced by sorafenib. Emerging evidence shows that triggering ferroptosis has potential as a cancer therapy. This work aimed to build a ferroptosis-related gene signature for predicting the outcome of LUAD.\nMETHODS: The TCGA-LUAD dataset was set as the training cohort, and the GSE72094 and GSE68465 datasets were set as the validation cohorts. Sixty-two ferroptosis-related genes were retrieved from the literature. A univariate Cox regression model was constructed for the training cohort to preliminarily screen for potential prognostic ferroptosis-related genes. A gene signature was generated from a LASSO Cox regression model and assessed with the training and validation cohorts through Kaplan-Meier, Cox, and ROC analyses. In addition, the correlation between the risk score and autophagy-related genes was determined by the Pearson test. Finally, GSEA and immune infiltrating analyses were performed to better study the functional annotation of the signature and the role of each kind of immune cell.\nRESULTS: A ten-gene signature was constructed from the training cohort and validated in three cohorts by Kaplan-Meier and Cox regression analyses, revealing its independent prognostic value in LUAD. Moreover, a ROC analysis conducted with all cohort data confirmed the predictive ability of the ten-gene signature for LUAD prognosis. A total of 62.85% (308/490) of autophagy-related genes were found to be significantly correlated with risk scores. GSEA detailed the exact pathways related to the gene signature, and immune-infiltrating analyses identified crucial roles for resting mast cells and resting dendritic cells in the prognosis of LUAD.\nCONCLUSIONS: We identified a novel ferroptosis-related ten-gene signature (PHKG2, PGD, PEBP1, NCOA4, GLS2, CISD1, ATP5G3, ALOX15, ALOX12B, and ACSL3) that can accurately predict LUAD prognosis and is closely linked to resting mast cells and resting dendritic cells.", "claims": [{"id": "claim-data-access", "statement": "The TCGA-LUAD dataset was chosen as the training cohort and downloaded from the GDC Xena Hub (https://gdc.xenahubs.net). 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This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE68465"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE68465"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34422970", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.21037/atm-20-7936", "sha256": "sha256:e7a68e5752a4517e78a6fce76ead1e5a37d230abd307fe575bf288c108d6382f", "bytes": 38851, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.21037/atm-20-7936", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8339871", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE68465", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE68465", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE68465", "version": null, "note": "The TCGA-LUAD dataset was chosen as the training cohort and downloaded from the GDC Xena Hub (https://gdc.xenahubs.net). 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"resolution_checked_at": "2026-11-01T15:39:55Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE72094", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE72094", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE72094", "version": null, "note": "The TCGA-LUAD dataset was chosen as the training cohort and downloaded from the GDC Xena Hub (https://gdc.xenahubs.net). Five hundred patients with LUAD in the TCGA-LUAD dataset who had both gene expression and survival data available were included in our research.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The TCGA-LUAD dataset was chosen as the training cohort and downloaded from the GDC Xena Hub (https://gdc.xenahubs.net). 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"240 (54.3%)", "220 (49.66%)"], ["Male", "230 (46%)", "202 (45.7%)", "223 (50.34%)"], ["T classification", "", "", ""], ["T1", "167 (33.4%)", "NA", "150 (33.86%)"], ["T2", "267 (53.4%)", "NA", "251 (56.66%)"], ["T3", "45 (9%)", "NA", "28 (6.32%)"], ["T4", "18 (3.6%)", "NA", "12 (2.71%)"], ["Unknown", "3 (0.6%)", "NA", "2 (0.45%)"], ["N classification", "", "", ""], ["N0", "324 (64.8%)", "NA", "299 (67.49%)"], ["N1", "94 (18.8%)", "NA", "88 (19.86%)"], ["N2", "69 (13.8%)", "NA", "53 (11.96%)"], ["N3", "2 (0.4%)", "NA", "0"], ["Unknown", "11 (2.2%)", "NA", "3 (0.68%)"], ["M classification", "", "", ""], ["M0", "332 (66.4%)", "NA", "NA"], ["M1", "24 (4.8%)", "NA", "NA"], ["Unknown", "144 (28.8%)", "NA", "NA"], ["Tumor stage", "", "", ""], ["Stage I", "268 (53.6%)", "265 (59.95%)", "NA"], ["Stage II", "119 (23.8%)", "69 (15.61%)", "NA"], ["Stage III", "80 (16%)", "63 (14.25%)", "NA"], ["Stage IV", "25 (5%)", "17 (3.85%)", "NA"], ["Unknown", "8 (1.6%)", "28 (6.33%)", "NA"], ["Race", "", "", ""], ["White", "386 (77.2%)", "399 (90.27%)", "295 (66.59%)"], ["Black or African American", "52 (10.4%)", "13 (2.94%)", "12 (2.71%)"], ["American Indian or Alaska Native", "1 (0.2%)", "0", "1 (0.23%)"], ["Asian", "7 (1.4%)", "3 (0.68%)", "6 (1.35%)"], ["Unknown", "54 (10.8%)", "27 (6.11%)", "129 (29.12%)"], ["Ethnicity", "", "", ""], ["Hispanic or Latino", "7 (1.4%)", "10 (2.26%)", "NA"], ["Not Hispanic or Latino", "381 (76.2%)", "402 (90.95%)", "NA"], ["Unknown", "112 (22.4%)", "30 (6.79%)", "NA"], ["Tobacco smoking history", "", "", ""], ["Ever", "415 (83%)", "335 (75.79%)", "300 (67.72%)"], ["Never", "71 (14.2%)", "33 (7.47%)", "49 (11.06%)"], ["Unknown", "14 (2.8%)", "74 (16.74%)", "94 (21.22%)"], ["Number pack-years smoked", "", "", ""], ["<30", "115 (23%)", "NA", "NA"], ["≥30", "227 (45.4%)", "NA", "NA"], ["Unknown", "158 (31.6%)", "NA", "NA"], ["Radiation therapy", "", "", ""], ["Yes", "58 (11.6%)", "NA", "65 (14.67%)"], ["No", "361 (72.2%)", "NA", "364 (82.17%)"], ["Unknown", "81 (16.2%)", "NA", "14 (3.16%)"], ["Chemotherapy", "", "", ""], ["Yes", "NA", "NA", "89 (20.09%)"], ["No", "NA", "NA", "341 (76.98%)"], ["Unknown", "NA", "NA", "13 (2.93%)"], ["Additional pharmaceutical therapy", "", ""], ["Yes", "61 (12.2%)", "NA", "NA"], ["No", "68 (13.6%)", "NA", "NA"], ["Unknown", "371 (74.2%)", "NA", "NA"], ["Additional radiation therapy", "", "", ""], ["Yes", "61 (12.2%)", "NA", "NA"], ["No", "71 (14.2%)", "NA", "NA"], ["Unknown", "368 (73.6%)", "NA", "NA"], ["EGFR mutation", "", "", ""], ["Yes", "80 (16%)", "47 (10.63%)", "NA"], ["No", "191 (38.2%)", "395 (89.37%)", "NA"], ["Unknown", "229 (45.8%)", "0", "NA"], ["KRAS mutation", "", "", ""], ["Yes", "23 (4.6%)", "154 (34.84%)", "NA"], ["No", "39 (7.8%)", "288 (65.16%)", "NA"], ["Unknown", "438 (87.6%)", "0", "NA"], ["STK11 mutation", "", "", ""], ["Yes", "NA", "68 (15.38%)", "NA"], ["No", "NA", "374 (84.62%)", "NA"], ["TP53 mutation", "", "", ""], ["Yes", "NA", "111 (25.11%)", "NA"], ["No", "NA", "331 (74.89%)", "NA"], ["EML4-ALK mutation", "", "", ""], ["Yes", "34 (6.8%)", "NA", "NA"], ["No", "207 (41.4%)", "NA", "NA"], ["Unknown", "259 (51.8%)", "NA", "NA"], ["Tumor intermediate dimension", "", ""], ["<1", "287 (57.4%)", "NA", "NA"], ["≥1", "88 (17.6%)", "NA", "NA"], ["Unknown", "125 (25%)", "NA", "NA"], ["Location in lung parenchyma", "", "", ""], ["Central lung", "62 (12.4%)", "NA", "NA"], ["Peripheral lung", "118 (23.6%)", "NA", "NA"], ["Unknown", "320 (64%)", "NA", "NA"], ["Person neoplasm cancer status", "", ""], ["With tumor", "134 (26.8%)", "NA", "NA"], ["Tumor free", "243 (48.6%)", "NA", "NA"], ["Unknown", "123 (24.6%)", "NA", "NA"], ["Vital status", "", "", ""], ["Alive", "318 (63.6%)", "298 (67.42%)", "207 (46.73%)"], ["Dead", "182 (36.4%)", "122 (27.6%)", "236 (53.27%)"], ["Unknown", "0", "22 (4.98%)", "NA"]], "row_count": 98, "column_count": 4, "numeric_cells": 143, "header_rows": 1, "locator": "section[10]/table-wrap[1]#t1"}}, {"id": "asset:table:pmid:34422970:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:af60f9de62ac4bb361a71c47a9ed9536397621443f7d9a8296ad931a5388110f", "bytes": 1757, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[11]/table-wrap[1]#t2", "version": null, "note": "14 ferroptosis-related potential prognostic genes generated from the training cohort", "structure": {"pmcid": "PMC8339871", "section_index": 11, "section_title": "Identification of a prognostic ferroptosis-related gene signature from the training cohort", "row_count": 16, "column_count": 6}, "table": {"label": "Table 2", "caption": "14 ferroptosis-related potential prognostic genes generated from the training cohort", "rows": [["Gene symbol", "Description", "HR", "95% confidence interval", "P value"], ["Lower", "Upper"], ["PEBP1", "Phosphatidylethanolamine-Binding Protein 1", "0.603658936", "0.464865289", "0.78389185", "0.000152746"], ["ACSL3", "Acyl-CoA Synthetase Long-Chain Family Member 3", "1.435108616", "1.157210163", "1.779743045", "0.001003251"], ["GLS2", "Glutaminase 2", "0.356469987", "0.176890046", "0.71836067", "0.003911814"], ["GCLC", "Glutamate-Cysteine Ligase Catalytic Subunit", "1.135847381", "1.034367787", "1.24728292", "0.007639188"], ["SLC7A11", "Solute Carrier Family 7 Member 11", "1.137868621", "1.023951703", "1.264459052", "0.016406631"], ["PHKG2", "Phosphorylase Kinase Catalytic Subunit Gamma 2", "0.69374619", "0.511654438", "0.940642238", "0.018577862"], ["PGD", "Phosphogluconate Dehydrogenase", "1.177966423", "1.02132216", "1.358635842", "0.02446422"], ["CISD1", "CDGSH Iron Sulfur Domain 1", "1.403301444", "1.041497232", "1.890792296", "0.025931782"], ["ALOX12B", "Arachidonate 12-Lipoxygenase, 12R Type", "1.528527805", "1.03748207", "2.251988076", "0.031866869"], ["DPP4", "Dipeptidyl Peptidase 4", "0.911077238", "0.836744384", "0.992013511", "0.031983077"], ["ALOX15", 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obtained from LASSO Cox regression model", "structure": {"pmcid": "PMC8339871", "section_index": 11, "section_title": "Identification of a prognostic ferroptosis-related gene signature from the training cohort", "row_count": 11, "column_count": 3}, "table": {"label": "Table 3", "caption": "10 ferroptosis-related prognostic genes obtained from LASSO Cox regression model", "rows": [["Gene symbol", "Description", "Risk coefficient"], ["PHKG2", "Phosphorylase Kinase Catalytic Subunit Gamma 2", "−0.376487238"], ["PGD", "Phosphogluconate Dehydrogenase", "0.027750809"], ["PEBP1", "Phosphatidylethanolamine Binding Protein 1", "−0.369553219"], ["NCOA4", "Nuclear Receptor Coactivator 4", "−0.498545244"], ["GLS2", "Glutaminase 2", "−0.399525822"], ["CISD1", "CDGSH Iron Sulfur Domain 1", "0.313326653"], ["ATP5G3", "ATP Synthase Membrane Subunit C Locus 3", "0.019018653"], ["ALOX15", "Arachidonate 15-Lipoxygenase", "−0.049973524"], ["ALOX12B", "Arachidonate 12-Lipoxygenase, 12R Type", "0.323899465"], ["ACSL3", "Acyl-CoA Synthetase Long Chain Family Member 3", "0.246495026"]], "row_count": 11, "column_count": 3, "numeric_cells": 21, "header_rows": 1, "locator": "section[11]/table-wrap[2]#t3"}}, {"id": "asset:table:pmid:34422970:4", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:f958976cfdaae725dac9f3b89b533f2f1ab7b0b3a4a3044246dc661fcd3105ff", "bytes": 7789, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[12]/table-wrap[1]#t4", "version": null, "note": "Univariate analysis and multivariate analysis of the correlation of gene signature risk score with outcomes among lung adenocarcinoma patients in three cohorts", "structure": {"pmcid": "PMC8339871", "section_index": 12, "section_title": "Prognostic ability of the ten-gene signature", "row_count": 67, "column_count": 10}, "table": {"label": "Table 4", "caption": "Univariate analysis and multivariate analysis of the correlation of gene signature risk score with outcomes among lung adenocarcinoma patients in three cohorts", "rows": [["Variable", "Univariate Cox analysis", "", "Multivariate Cox analysis"], ["coef", "HR (95% CI)", "z", "P value", "coef", "HR (95% CI)", "z", "P value"], ["TCGA-LUAD (overall survival)^", "", "", "", "", "", "", "", "", ""], ["Gender (male vs. female)", "0.048", "1.05 (0.784–1.4)", "0.322", "7.47E-01", "", "", "", "", ""], ["Age", "0.00816", "1.01 (0.993–1.02)", "1.05", "2.94E-01", "", "", "", "", ""], ["Tumor stage II (vs. stage I)", "0.905", "2.47 (1.72–3.56)", "4.87", "1.09E-06*", "", "1.32", "3.75 (1.44–9.8)", "2.7", "6.93E-03"], ["Tumor stage III (vs. stage I)", "1.25", "3.49 (2.38–5.12)", "6.4", "1.51E-10*", "", "0.455", "1.58 (0.445–5.59)", "0.705", "4.81E-01"], ["Tumor stage IV (vs. stage I)", "1.34", "3.82 (2.2–6.62)", "4.76", "1.92E-06*", "", "−0.107", "0.899 (0.255–3.17)", "−0.166", "8.68E-01"], ["Tobacco smoking history (ever vs. never)", "−0.127", "0.88 (0.583–1.33)", "−0.605", "5.45E-01", "", "", "", "", ""], ["Number pack years smoked", "0.00327", "1 (0.996–1.01)", "0.938", "3.48E-01", "", "", "", "", ""], ["Race (White vs. non-White)", "0.36", "1.43 (0.875–2.34)", "1.43", "1.53E-01", "", "", "", "", ""], ["Ethnicity (Hispanic or Latino vs. Non-Hispanic or Latino)", "0.387", "1.47 (0.466–4.65)", "0.658", "5.10E-01", "", "", "", "", ""], ["Tumor intermediate dimension", "0.441", "1.55 (0.922–2.62)", "1.65", "9.80E-02", "", "", "", "", ""], ["Radiation therapy (yes vs. no)", "0.763", "2.14 (1.44–3.19)", "3.76", "1.73E-04*", "", "0.446", "1.56 (0.415–5.88)", "0.66", "5.09E-01"], ["Additional pharmaceutical therapy (yes vs. no)", "−0.502", "0.605 (0.382–0.959)", "−2.14", "3.26E-02*", "", "−1.03", "0.356 (0.158–0.8)", "−2.5", "1.25E-02*"], ["Additional radiation therapy (yes vs. no)", "−0.0153", "0.985 (0.625–1.55)", "−0.0661", "9.47E-01", "", "", "", "", ""], ["Location in lung parenchyma (central lung vs. peripheral lung)", "0.0908", "1.09 (0.684–1.75)", "0.378", "7.06E-01", "", "", "", "", ""], ["KRAS mutation (yes vs. no)", "0.492", "1.63 (0.672–3.98)", "1.08", "2.78E-01", "", "", "", "", ""], ["EGFR mutation (yes vs. no)", "0.268", "1.31 (0.828–2.06)", "1.15", "2.50E-01", "", "", "", "", ""], ["EML4-ALK mutation (yes vs. no)", "0.592", "1.81 (1.01–3.24)", "1.98", "4.73E-02*", "", "1.18", "3.25 (1.22–8.63)", "2.36", "1.84E-02*"], ["Risk score", "1.22", "3.39 (2.49–4.62)", "7.76", "8.78E-15*", "", "1.99", "7.32 (2.88–18.6)", "4.18", "2.94E-05*"], ["TCGA-LUAD (progression-free survival)#", "", "", "", "", "", "", "", "", ""], ["Gender (male vs. female)", "0.07", "1.07 (0.815–1.41)", "0.499", "6.17E-01", "", "", "", "", ""], ["Age", "−0.000998", "0.999 (0.985–1.01)", "−0.141", "8.88E-01", "", "", "", "", ""], ["Tumor stage II (vs. stage I)", "0.798", "2.22 (1.61–3.07)", "4.85", "1.22E-06*", "", "1.2", "3.33 (1.92–5.78)", "4.28", "1.88E-05*"], ["Tumor stage III (vs. 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"1.67E-02*"], ["Age", "0.00696", "1.01 (0.988–1.03)", "0.702", "4.83E-01", "", "", "", "", ""], ["Race (White vs. non-White)", "−0.0694", "0.933 (0.38–2.29)", "−0.151", "8.80E-01", "", "", "", "", ""], ["Ethnicity (Hispanic or Latino vs. non-Hispanic or Latino)", "−0.642", "0.526 (0.0733–3.78)", "−0.638", "5.24E-01", "", "", "", "", ""], ["Tobacco smoking history (ever vs. never)", "0.314", "1.37 (0.597–3.14)", "0.741", "4.59E-01", "", "", "", "", ""], ["Tumor stage II (vs. stage I)", "0.758", "2.13 (1.32–3.44)", "3.11", "1.85E-03*", "", "0.708", "2.03 (1.25–3.28)", "2.88", "3.92E-03*"], ["Tumor stage III (vs. stage I)", "1.13", "3.09 (1.93–4.97)", "4.67", "3.00E-06*", "", "1.17", "3.22 (1.99–5.22)", "4.76", "1.91E-06*"], ["Tumor stage IV (vs. stage I)", "1.21", "3.35 (1.59–7.06)", "3.18", "1.48E-03*", "", "1.14", "3.13 (1.48–6.62)", "2.99", "2.80E-03*"], ["KRAS mutation (yes vs. no)", "0.376", "1.46 (1–2.12)", "1.97", "4.92E-02*", "", "0.157", "1.17 (0.796–1.72)", "0.799", 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