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pmid:38647237
Development of m6A/m5C/m1A regulated lncRNA signature for prognostic prediction, personalized immune intervention and drug selection in LUAD.
Chao Ma · Zhuoyu Gu · Yang Yang
Journal of cellular and molecular medicine · 2024 doi:10.1111/jcmm.18282
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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The TCGA-LUAD dataset was used as for signature training, while the validation cohort was created by amalgamating publicly accessible GEO datasets including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081. The study focused on 33 genes that are regulated by m6A, m5C or m1A (mRG), which were used to form mRGs clusters and clusters of mRG differentially expressed genes clusters (mRG-DEG clusters). Our subsequent LASSO regression analysis trained the signature of m6A/m5C/m1A-related lncRNA (mRLncSig) using lncRNAs that exhibited differential expression among mRG-DEG clusters and had prognostic value. The model's accuracy underwent validation via Kaplan-Meier analysis, Cox regression, ROC analysis, tAUC evaluation, PCA examination and nomogram predictor validation. In evaluating the immunotherapeutic potential of the signature, we employed multiple bioinformatics algorithms and concepts through various analyses. These included seven newly developed immunoinformatic algorithms, as well as evaluations of TMB, TIDE and immune checkpoints. Additionally, we identified and validated promising agents that target the high-risk mRLncSig in LUAD. To validate the real-world expression pattern of mRLncSig, real-time PCR was carried out on human LUAD tissues. The signature's ability to perform in pan-cancer settings was also evaluated. The study created a 10-lncRNA signature, mRLncSig, which was validated to have prognostic power in the validation cohort. Real-time PCR was applied to verify the actual manifestation of each gene in the signature in the real world. Our immunotherapy analysis revealed an association between mRLncSig and immune status. mRLncSig was found to be closely linked to several checkpoints, such as IL10, IL2, CD40LG, SELP, BTLA and CD28, which could be appropriate immunotherapy targets for LUAD. Among the high-risk patients, our study identified 12 candidate drugs and verified gemcitabine as the most significant one that could target our signature and be effective in treating LUAD. Additionally, we discovered that some of the lncRNAs in mRLncSig could play a crucial role in certain cancer types, and thus, may require further attention in future studies. According to the findings of this study, the use of mRLncSig has the potential to aid in forecasting the prognosis of LUAD and could serve as a potential target for immunotherapy. 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The sources of publicly available data are listed below. Model training utilized data from the TCGA and pan‐cancer TCGA TARGET GTEx, which were obtained from https://xenabrowser.net. The validation data came from GEO datasets, including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081, which were downloaded from https://www.ncbi.nlm.nih.gov/geo. For drug prediction, the CTRP and PRISM databases were used and obtained from https://portals.broadinstitute.org/ctrp and https://depmap.org/portal/prism, respectively. To obtain the laboratory data used in this study, please contact the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The study utilized data from both public databases and laboratory experiments. The sources of publicly available data are listed below. Model training utilized data from the TCGA and pan‐cancer TCGA TARGET GTEx, which were obtained from https://xenabrowser.net. The validation data came from GEO datasets, including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081, which were downloaded from https://www.ncbi.nlm.nih.gov/geo. For drug prediction, the CTRP and PRISM databases were used and obtained from https://portals.broadinstitute.org/ctrp and https://depmap.org/portal/prism, respectively. To obtain the laboratory data used in this study, please contact the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM773540", "GSM773541", "GSM773542", "GSM773543", "GSM773544", "GSM773545", "GSM773546", "GSM773547", "GSM773548", "GSM773549", "GSM773550", "GSM773551", "GSM773552", "GSM773553", "GSM773554", "GSM773555", "GSM773556", "GSM773557", "GSM773558", "GSM773559", "GSM773560", "GSM773561", "GSM773562", "GSM773563", "GSM773564", "GSM773565", "GSM773566", "GSM773567", "GSM773568", "GSM773569", "GSM773570", "GSM773571", "GSM773572", "GSM773573", "GSM773574", "GSM773575", "GSM773576", "GSM773577", "GSM773578", "GSM773579", "GSM773580", "GSM773581", "GSM773582", "GSM773583", "GSM773584", "GSM773585", "GSM773586", "GSM773587", "GSM773588", "GSM773589", "GSM773590", "GSM773591", "GSM773592", "GSM773593", "GSM773594", "GSM773595", "GSM773596", "GSM773597", "GSM773598", "GSM773599", "GSM773600", "GSM773601", "GSM773602", "GSM773603", "GSM773604", "GSM773605", "GSM773606", "GSM773607", "GSM773608", "GSM773609", "GSM773610", "GSM773611", "GSM773612", "GSM773613", "GSM773614", "GSM773615", "GSM773616", "GSM773617", "GSM773618", "GSM773619", "GSM773620", "GSM773621", "GSM773622", "GSM773623", "GSM773624", "GSM773625", "GSM773626", "GSM773627", "GSM773628", "GSM773629", "GSM773630", "GSM773631", "GSM773632", "GSM773633", "GSM773634", "GSM773635", "GSM773636", "GSM773637", "GSM773638", "GSM773639", "GSM773640", "GSM773641", "GSM773642", "GSM773643", "GSM773644", "GSM773645", "GSM773646", "GSM773647", "GSM773648", "GSM773649", "GSM773650", "GSM773651", "GSM773652", "GSM773653", "GSM773654", "GSM773655", "GSM773656", "GSM773657", "GSM773658", "GSM773659", "GSM773660", "GSM773661", "GSM773662", "GSM773663", "GSM773664", "GSM773665", "GSM773666", "GSM773667", "GSM773668", "GSM773669", "GSM773670", "GSM773671", "GSM773672", "GSM773673", "GSM773674", "GSM773675", "GSM773676", "GSM773677", "GSM773678", "GSM773679", "GSM773680", "GSM773681", "GSM773682", "GSM773683", "GSM773684", "GSM773685", "GSM773686", "GSM773687", "GSM773688", "GSM773689", "GSM773690", "GSM773691", "GSM773692", "GSM773693", "GSM773694", "GSM773695", "GSM773696", "GSM773697", "GSM773698", "GSM773699", "GSM773700", "GSM773701", "GSM773702", "GSM773703", "GSM773704", "GSM773705", "GSM773706", "GSM773707", "GSM773708", "GSM773709", "GSM773710", "GSM773711", "GSM773712", "GSM773713", "GSM773714", "GSM773715", "GSM773716", "GSM773717", "GSM773718", "GSM773719", "GSM773720", "GSM773721", "GSM773722", "GSM773723", "GSM773724", "GSM773725", "GSM773726", "GSM773727", "GSM773728", "GSM773729", "GSM773730", "GSM773731", "GSM773732", "GSM773733", "GSM773734", "GSM773735", "GSM773736", "GSM773737", "GSM773738", "GSM773739", "GSM773740", "GSM773741", "GSM773742", "GSM773743", "GSM773744", "GSM773745", "GSM773746", "GSM773747", "GSM773748", "GSM773749", "GSM773750", "GSM773751", "GSM773752", "GSM773753", "GSM773754", "GSM773755", "GSM773756", "GSM773757", "GSM773758", "GSM773759", "GSM773760", "GSM773761", "GSM773762", "GSM773763", "GSM773764", "GSM773765", "GSM773766", "GSM773767", "GSM773768", "GSM773769", "GSM773770", "GSM773771", "GSM773772", "GSM773773", "GSM773774", "GSM773775", "GSM773776", "GSM773777", "GSM773778", "GSM773779", "GSM773780", "GSM773781", "GSM773782", "GSM773783", "GSM773784", "GSM773785"], "sample_count": 246, "group_sizes": null, "group_sizes_basis": null, "platform": "570", "taxon": "Homo sapiens", "title": "Gene expression data for pathological stage I-II lung adenocarcinomas", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE37745", "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=GSE37745", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE37745", "version": null, "note": "The study utilized data from both public databases and laboratory experiments. The sources of publicly available data are listed below. Model training utilized data from the TCGA and pan‐cancer TCGA TARGET GTEx, which were obtained from https://xenabrowser.net. The validation data came from GEO datasets, including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081, which were downloaded from https://www.ncbi.nlm.nih.gov/geo. For drug prediction, the CTRP and PRISM databases were used and obtained from https://portals.broadinstitute.org/ctrp and https://depmap.org/portal/prism, respectively. To obtain the laboratory data used in this study, please contact the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The study utilized data from both public databases and laboratory experiments. The sources of publicly available data are listed below. Model training utilized data from the TCGA and pan‐cancer TCGA TARGET GTEx, which were obtained from https://xenabrowser.net. The validation data came from GEO datasets, including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081, which were downloaded from https://www.ncbi.nlm.nih.gov/geo. For drug prediction, the CTRP and PRISM databases were used and obtained from https://portals.broadinstitute.org/ctrp and https://depmap.org/portal/prism, respectively. To obtain the laboratory data used in this study, please contact the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1019138", "GSM1019139", "GSM1019140", "GSM1019141", "GSM1019142", "GSM1019143", "GSM1019144", "GSM1019145", "GSM1019146", "GSM1019147", "GSM1019148", "GSM1019149", "GSM1019150", "GSM1019151", "GSM1019152", "GSM1019153", "GSM1019154", "GSM1019155", "GSM1019156", "GSM1019157", "GSM1019158", "GSM1019159", "GSM1019160", "GSM1019161", "GSM1019162", "GSM1019163", "GSM1019164", "GSM1019165", "GSM1019166", "GSM1019167", "GSM1019168", "GSM1019169", "GSM1019170", "GSM1019171", "GSM1019172", "GSM1019173", "GSM1019174", "GSM1019175", "GSM1019176", "GSM1019177", "GSM1019178", "GSM1019179", "GSM1019180", "GSM1019181", "GSM1019182", "GSM1019183", "GSM1019184", "GSM1019185", "GSM1019186", "GSM1019187", "GSM1019188", "GSM1019189", "GSM1019190", "GSM1019191", "GSM1019192", "GSM1019193", "GSM1019194", "GSM1019195", "GSM1019196", "GSM1019197", "GSM1019198", "GSM1019199", "GSM1019200", "GSM1019201", "GSM1019202", "GSM1019203", "GSM1019204", "GSM1019205", "GSM1019206", "GSM1019207", "GSM1019208", "GSM1019209", "GSM1019210", "GSM1019211", "GSM1019212", "GSM1019213", "GSM1019214", "GSM1019215", "GSM1019216", "GSM1019217", "GSM1019218", "GSM1019219", "GSM1019220", "GSM1019221", "GSM1019222", "GSM1019223", "GSM1019224", "GSM1019225", "GSM1019226", "GSM1019227", "GSM1019228", "GSM1019229", "GSM1019230", "GSM1019231", "GSM1019232", "GSM1019233", "GSM1019234", "GSM1019235", "GSM1019236", "GSM1019237", "GSM1019238", "GSM1019239", "GSM1019240", "GSM1019241", "GSM1019242", "GSM1019243", "GSM1019244", "GSM1019245", "GSM1019246", "GSM1019247", "GSM1019248", "GSM1019249", "GSM1019250", "GSM1019251", "GSM1019252", "GSM1019253", "GSM1019254", "GSM1019255", "GSM1019256", "GSM1019257", "GSM1019258", "GSM1019259", "GSM1019260", "GSM1019261", "GSM1019262", "GSM1019263", "GSM1019264", "GSM1019265", "GSM1019266", "GSM1019267", "GSM1019268", "GSM1019269", "GSM1019270", "GSM1019271", "GSM1019272", "GSM1019273", "GSM1019274", "GSM1019275", "GSM1019276", "GSM1019277", "GSM1019278", "GSM1019279", "GSM1019280", "GSM1019281", "GSM1019282", "GSM1019283", "GSM1019284", "GSM1019285", "GSM1019286", "GSM1019287", "GSM1019288", "GSM1019289", "GSM1019290", "GSM1019291", "GSM1019292", "GSM1019293", "GSM1019294", "GSM1019295", "GSM1019296", "GSM1019297", "GSM1019298", "GSM1019299", "GSM1019300", "GSM1019301", "GSM1019302", "GSM1019303", "GSM1019304", "GSM1019305", "GSM1019306", "GSM1019307", "GSM1019308", "GSM1019309", "GSM1019310", "GSM1019311", "GSM1019312", "GSM1019313", "GSM1019314", "GSM1019315", "GSM1019316", "GSM1019317", "GSM1019318", "GSM1019319", "GSM1019320", "GSM1019321", "GSM1019322", "GSM1019323", "GSM1019324", "GSM1019325", "GSM1019326", "GSM1019327", "GSM1019328", "GSM1019329", "GSM1019330", "GSM1019331", "GSM1019332", "GSM1019333"], "sample_count": 196, "group_sizes": null, "group_sizes_basis": null, "platform": "570", "taxon": "Homo sapiens", "title": "Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis and tissue microarray validation", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE50081", "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=GSE50081", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE50081", "version": null, "note": "The study utilized data from both public databases and laboratory experiments. The sources of publicly available data are listed below. Model training utilized data from the TCGA and pan‐cancer TCGA TARGET GTEx, which were obtained from https://xenabrowser.net. The validation data came from GEO datasets, including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081, which were downloaded from https://www.ncbi.nlm.nih.gov/geo. For drug prediction, the CTRP and PRISM databases were used and obtained from https://portals.broadinstitute.org/ctrp and https://depmap.org/portal/prism, respectively. To obtain the laboratory data used in this study, please contact the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The study utilized data from both public databases and laboratory experiments. The sources of publicly available data are listed below. Model training utilized data from the TCGA and pan‐cancer TCGA TARGET GTEx, which were obtained from https://xenabrowser.net. The validation data came from GEO datasets, including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081, which were downloaded from https://www.ncbi.nlm.nih.gov/geo. For drug prediction, the CTRP and PRISM databases were used and obtained from https://portals.broadinstitute.org/ctrp and https://depmap.org/portal/prism, respectively. To obtain the laboratory data used in this study, please contact the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1213669", "GSM1213670", "GSM1213671", "GSM1213672", "GSM1213673", "GSM1213674", "GSM1213675", "GSM1213676", "GSM1213677", "GSM1213678", "GSM1213679", "GSM1213680", "GSM1213681", "GSM1213682", "GSM1213683", "GSM1213684", "GSM1213685", "GSM1213686", "GSM1213687", "GSM1213688", "GSM1213689", "GSM1213690", "GSM1213691", "GSM1213692", "GSM1213693", "GSM1213694", "GSM1213695", "GSM1213696", "GSM1213697", "GSM1213698", "GSM1213699", "GSM1213700", "GSM1213701", "GSM1213702", "GSM1213703", "GSM1213704", "GSM1213705", "GSM1213706", "GSM1213707", "GSM1213708", "GSM1213709", "GSM1213710", "GSM1213711", "GSM1213712", "GSM1213713", "GSM1213714", "GSM1213715", "GSM1213716", "GSM1213717", "GSM1213718", "GSM1213719", "GSM1213720", "GSM1213721", "GSM1213722", "GSM1213723", "GSM1213724", "GSM1213725", "GSM1213726", "GSM1213727", "GSM1213728", "GSM1213729", "GSM1213730", "GSM1213731", "GSM1213732", "GSM1213733", "GSM1213734", "GSM1213735", "GSM1213736", "GSM1213737", "GSM1213738", "GSM1213739", "GSM1213740", "GSM1213741", "GSM1213742", "GSM1213743", "GSM1213744", "GSM1213745", "GSM1213746", "GSM1213747", "GSM1213748", "GSM1213749", "GSM1213750", "GSM1213751", "GSM1213752", "GSM1213753", "GSM1213754", "GSM1213755", "GSM1213756", "GSM1213757", "GSM1213758", "GSM1213759", "GSM1213760", "GSM1213761", "GSM1213762", "GSM1213763", "GSM1213764", "GSM1213765", "GSM1213766", "GSM1213767", "GSM1213768", "GSM1213769", "GSM1213770", "GSM1213771", "GSM1213772", "GSM1213773", "GSM1213774", "GSM1213775", "GSM1213776", "GSM1213777", "GSM1213778", "GSM1213779", "GSM1213780", "GSM1213781", "GSM1213782", "GSM1213783", "GSM1213784", "GSM1213785", "GSM1213786", "GSM1213787", "GSM1213788", "GSM1213789", "GSM1213790", "GSM1213791", "GSM1213792", "GSM1213793", "GSM1213794", "GSM1213795", "GSM1213796", "GSM1213797", "GSM1213798", "GSM1213799", "GSM1213800", "GSM1213801", "GSM1213802", "GSM1213803", "GSM1213804", "GSM1213805", "GSM1213806", "GSM1213807", "GSM1213808", "GSM1213809", "GSM1213810", "GSM1213811", "GSM1213812", "GSM1213813", "GSM1213814", "GSM1213815", "GSM1213816", "GSM1213817", "GSM1213818", "GSM1213819", "GSM1213820", "GSM1213821", "GSM1213822", "GSM1213823", "GSM1213824", "GSM1213825", "GSM1213826", "GSM1213827", "GSM1213828", "GSM1213829", "GSM1213830", "GSM1213831", "GSM1213832", "GSM1213833", "GSM1213834", "GSM1213835", "GSM1213836", "GSM1213837", "GSM1213838", "GSM1213839", "GSM1213840", "GSM1213841", "GSM1213842", "GSM1213843", "GSM1213844", "GSM1213845", "GSM1213846", "GSM1213847", "GSM1213848", "GSM1213849"], "sample_count": 181, "group_sizes": null, "group_sizes_basis": null, "platform": "570", "taxon": "Homo sapiens", "title": "Validation of a histology-independent prognostic gene signature for early stage, non-small cell lung cancer including stage IA patients", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE29013 not downloaded", "asset:data:geo:GSE29013 licence not read", "asset:data:geo:GSE30219 not downloaded", "asset:data:geo:GSE30219 licence not read", "asset:data:geo:GSE31210 not downloaded", "asset:data:geo:GSE31210 licence not read", "asset:data:geo:GSE37745 not downloaded", "asset:data:geo:GSE37745 licence not read", "asset:data:geo:GSE50081 not downloaded", "asset:data:geo:GSE50081 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "survival_analysis", "specific": "kaplan_meier", "label": "Survival analysis", "dsl_operations": ["survival_km"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.7, "band": "medium", "quote": "Kaplan-Meier"}}, {"id": "method-2", "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": 0.7, "band": "medium", "quote": "Cox regression"}}, {"id": "method-3", "family": "principal_component_analysis", "specific": "pca", "label": "Principal component analysis", "dsl_operations": ["pca_fit"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["wide_numeric_matrix"], "evidence": {"score": 0.7, "band": "medium", "quote": "PCA"}}, {"id": "method-4", "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-5", "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 analysis"}}, {"id": "method-6", "family": null, "specific": null, "label": "LASSO analysis", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "verbatim", "quote": "To further refine our findings, we carried out LASSO analysis using these 18 DELs for selection and shrinkage."}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "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": ["survival_km"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: kaplan_meier."}, "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": ["GSE29013", "GSE30219", "GSE31210", "GSE37745", "GSE50081"], "resolved_accessions": ["GSE29013", "GSE30219", "GSE31210", "GSE37745", "GSE50081"], "statements": ["The study utilized data from both public databases and laboratory experiments. The sources of publicly available data are listed below. Model training utilized data from the TCGA and pan‐cancer TCGA TARGET GTEx, which were obtained from https://xenabrowser.net. The validation data came from GEO datasets, including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081, which were downloaded from https://www.ncbi.nlm.nih.gov/geo. For drug prediction, the CTRP and PRISM databases were used and obtained from https://portals.broadinstitute.org/ctrp and https://depmap.org/portal/prism, respectively. To obtain the laboratory data used in this study, please contact the corresponding author."], "basis": "The paper names GSE29013, GSE30219, GSE31210, GSE37745, GSE50081 in Gene Expression Omnibus and the accession resolves in the repository. 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