Identification and Mechanism of the PD-1/PD-L1 Genomic Signature SORL1 as Protective Factor in Bladder Cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34976002", "kind": "science-record", "revision": 4, "content_hash": "sha256:6b929f40d2b67d473b11e74f50e89b71f4f8c51adb360b966d31d7e3fee8d700", "created_at": "2026-11-01T17:36:41Z", "updated_at": "2026-11-01T22:48:09Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Identification and Mechanism of the PD-1/PD-L1 Genomic Signature SORL1 as Protective Factor in Bladder Cancer.", "doi": "10.3389/fgene.2021.736158", "pmid": "34976002", "authors": ["Yajing Xu", "Didi Chen", "Lanxiao Shen", "Xiaowei Huang", "Yi Chen", "Huafang Su"], "journal": "Frontiers in genetics", "year": 2021, "abstract": "Background: Immunotherapy has recently shown remarkable efficacy for advanced bladder cancer patients. Accordingly, identifying a biomarker associated with the programmed cell death protein 1 (PD-1)/its ligand (PD-L1) genomic signature to predict patient prognosis is necessary. Methods: In this study, we used mutation data and RNA-seq data of bladder cancer samples acquired from The Cancer Genome Atlas (TCGA) database to combine PD-1/PD-L1-associated mutational signatures with PD-1/PD-L1-associated differentially expressed genes (DEGs). Then, we performed a Kaplan-Meier analysis on the corresponding clinical data of the TCGA bladder urothelial carcinoma (BLCA) cohort to identify prognostic genes, and the results were validated using the GSE48075 cohort. The online platform UCSC Xena was used to analyze the relationship between the candidate genes and clinical parameters. We utilized the Human Protein Atlas (HPA) database to validate the protein expression levels. Then, correlation analysis, cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) analysis, and gene set enrichment analysis (GSEA) were used to clarify the mechanism. Results: We identified one prognostic gene, sortilin related receptor 1 (SORL1), whose downregulation was associated with a comparatively advanced BLCA stage. While further exploring this finding, we found that SORL1 expression was negatively correlated with PD-1/PD-L1 expression and M2 macrophage levels. Furthermore, we found that the downregulation of SORL1 expression was significantly associated with a higher epithelial-mesenchymal transition (EMT) score. Conclusion: We described a novel PD-1/PD-L1-associated signature, SORL1, that predicts favorable outcomes in bladder cancer. SORL1 might reduce immune suppression and inhibit the M2 macrophage-induced EMT phenotype of tumor cells.", "claims": [{"id": "claim-method", "statement": "Based on the 401 TCGA BLCA samples with available RNA-seq data and clinical information, we performed a Kaplan-Meier analysis of the overall survival (OS) rates to screen genes related to prognosis from the PD-1/PD-L1 genomic signatures.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34976002", "locator": "sections[7] \"Prognosis Analysis for PD-1/PD-L1 Genomic Signatures\" paragraph 2", "quote": "Based on the 401 TCGA BLCA samples with available RNA-seq data and clinical information, we performed a Kaplan-Meier analysis of the overall survival (OS) rates to screen genes related to prognosis from the PD-1/PD-L1 genomic signatures."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34976002", "locator": "sections[24] \"Data Availability Statement\" paragraph 2", "quote": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The paper used Kaplan-Meier analysis of TCGA BLCA clinical data, validated in the GSE48075 cohort, and identified SORL1 expression as a favorable prognostic indicator.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:34976002", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "Then, we performed a Kaplan-Meier analysis on the corresponding clinical data of the TCGA bladder urothelial carcinoma (BLCA) cohort to identify prognostic genes, and the results were validated using the GSE48075 cohort."}, {"asset": "source:pmid:34976002", "locator": "sections[16] \"SORL1 Expression Predicts Favorable Prognosis in Bladder Cancer\" paragraph 2", "quote": "In summary, SORL1 was identified as the only good prognostic indicator for BLCA overall survival outcomes."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The paper used Kaplan-Meier analysis of TCGA BLCA clinical data, validated in the GSE48075 cohort, and identified SORL1 expression as a favorable prognostic indicator.", "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:34976002"], "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. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE48075"], "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:GSE48075"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34976002", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fgene.2021.736158", "sha256": "sha256:a1169f76ca2f38ea8abe91a1c702c4d2e6f1b1df38447994c63af402f63bc328", "bytes": 34265, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fgene.2021.736158", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8716752", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE48075", "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=GSE48075", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE48075", "version": null, "note": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1167333", "GSM1167334", "GSM1167335", "GSM1167336", "GSM1167337", "GSM1167338", "GSM1167339", "GSM1167340", "GSM1167341", "GSM1167342", "GSM1167343", "GSM1167344", "GSM1167345", "GSM1167346", "GSM1167347", "GSM1167348", "GSM1167349", "GSM1167350", "GSM1167351", "GSM1167352", "GSM1167353", "GSM1167354", "GSM1167355", "GSM1167356", "GSM1167357", "GSM1167358", "GSM1167359", "GSM1167360", "GSM1167361", "GSM1167362", "GSM1167363", "GSM1167364", "GSM1167365", "GSM1167366", "GSM1167367", "GSM1167368", "GSM1167369", "GSM1167370", "GSM1167371", "GSM1167372", "GSM1167373", "GSM1167374", "GSM1167375", "GSM1167376", "GSM1167377", "GSM1167378", "GSM1167379", "GSM1167380", "GSM1167381", "GSM1167382", "GSM1167383", "GSM1167384", "GSM1167385", "GSM1167386", "GSM1167387", "GSM1167388", "GSM1167389", "GSM1167390", "GSM1167391", "GSM1167392", "GSM1167393", "GSM1167394", "GSM1167395", "GSM1167396", "GSM1167397", "GSM1167398", "GSM1167399", "GSM1167400", "GSM1167401", "GSM1167402", "GSM1167403", "GSM1167404", "GSM1167405", "GSM1167406", "GSM1167407", "GSM1167408", "GSM1167409", "GSM1167410", "GSM1167411", "GSM1167412", "GSM1167413", "GSM1167414", "GSM1167415", "GSM1167416", "GSM1167417", "GSM1167418", "GSM1167419", "GSM1167420", "GSM1167421", "GSM1167422", "GSM1167423", "GSM1167424", "GSM1167425", "GSM1167426", "GSM1167427", "GSM1167428", "GSM1167429", "GSM1167430", "GSM1167431", "GSM1167432", "GSM1167433", "GSM1167434", "GSM1167435", "GSM1167436", "GSM1167437", "GSM1167438", "GSM1167439", "GSM1167440", "GSM1167441", "GSM1167442", "GSM1167443", "GSM1167444", "GSM1167445", "GSM1167446", "GSM1167447", "GSM1167448", "GSM1167449", "GSM1167450", "GSM1167451", "GSM1167452", "GSM1167453", "GSM1167454", "GSM1167455", "GSM1167456", "GSM1167457", "GSM1167458", "GSM1167459", "GSM1167460", "GSM1167461", "GSM1167462", "GSM1167463", "GSM1167464", "GSM1167465", "GSM1167466", "GSM1167467", "GSM1167468", "GSM1167469", "GSM1167470", "GSM1167471", "GSM1167472", "GSM1167473", "GSM1167474"], "sample_count": 142, "group_sizes": null, "group_sizes_basis": null, "platform": "6947", "taxon": "Homo sapiens", "title": "Identification of subsets of urothelial carcinoma", "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:GSE48075 not downloaded", "asset:data:geo:GSE48075 licence not read"]}, "analysis": {"state": "complete", "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": 1.0, "band": "verbatim", "quote": "Based on the 401 TCGA BLCA samples with available RNA-seq data and clinical information, we performed a Kaplan-Meier analysis of the overall survival (OS) rates to screen genes related to prognosis from the PD-1/PD-L1 genomic signatures."}}], "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", "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": ["GSE48075"], "resolved_accessions": ["GSE48075"], "statements": ["The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors."], "basis": "The paper names GSE48075 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": ["survival_km"], "assets": ["source:pmid:34976002", "data:geo:GSE48075"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE48075"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T17:13:42Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 10467, "completion_tokens": 1284, "cached_tokens": 256}}, "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:34976002", "type": "paper", "label": "pmid:34976002"}, {"id": "source:pmid:34976002", "type": "manuscript", "label": "PMID 34976002 full text"}, {"id": "data:geo:GSE48075", "type": "dataset", "label": "GEO GSE48075"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:34976002", "type": "paper", "label": "pmid:34976002"}, {"id": "source:pmid:34976002", "type": "manuscript", "label": "PMID 34976002 full text"}, {"id": "data:geo:GSE48075", "type": "dataset", "label": "GEO GSE48075"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-34976002", "type": "extraction", "used": ["source:pmid:34976002"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE48075", "type": "accession_resolution", "used": ["data:geo:GSE48075"], "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:34976002", "parent_hash": "sha256:ad2bc3625c76b6e5615abf9b5f0375b2ab5520762fd5008c716f55690f03fffa", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE48075 licence not read", "asset:data:geo:GSE48075 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ds: In this study, we used mutation data and RNA-seq data of bladder cancer samples acquired from"], "order_basis": "paper_text_order:395", "id": "assay:1"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["survival_km"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Based on the 401 TCGA BLCA samples with available RNA-seq data and clinical information, we performed a Kaplan-Meier analysis of the overall survival (OS) rates to screen genes related to prognosis from the PD-1/PD-L1 genomic signatures."], "order_basis": "consumes_earlier_output", "id": "assay:2"}]}