Novel Hypoxia-Related Gene Signature for Risk Stratification and Prognosis in Hepatocellular Carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34194464", "kind": "science-record", "revision": 7, "content_hash": "sha256:fa1075dc2f2ebe32ea776a2c64b7698d1ec618627943d222f9b9d840379d4d81", "created_at": "2026-11-01T15:41:41Z", "updated_at": "2026-11-01T22:04:05Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Novel Hypoxia-Related Gene Signature for Risk Stratification and Prognosis in Hepatocellular Carcinoma.", "doi": "10.3389/fgene.2021.613890", "pmid": "34194464", "authors": ["Quanxiao Li", "Limin Jin", "Meng Jin"], "journal": "Frontiers in genetics", "year": 2021, "abstract": "Hepatocellular carcinoma (HCC) is the most common form of liver cancer with limited therapeutic options and low survival rate. The hypoxic microenvironment plays a vital role in progression, metabolism, and prognosis of malignancies. Therefore, this study aims to develop and validate a hypoxia gene signature for risk stratification and prognosis prediction of HCC patients. The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases were used as a training cohort, and one Gene Expression Omnibus database (GSE14520) was served as an external validation cohort. Our results showed that eight hypoxia-related genes (HRGs) were identified by the least absolute shrinkage and selection operator analysis to develop the hypoxia gene signature and demarcated HCC patients into the high- and low-risk groups. In TCGA, ICGC, and GSE14520 datasets, patients in the high-risk group had worse overall survival outcomes than those in the low-risk group (all log-rank P < 0.001). Besides, the risk score derived from the hypoxia gene signature could serve as an independent prognostic factor for HCC patients in the three independent datasets. Finally, a nomogram including the gene signature and tumor-node-metastasis stage was constructed to serve clinical practice. In the present study, a novel hypoxia signature risk model could reflect individual risk classification and provide therapeutic targets for patients with HCC. The prognostic nomogram may help predict individualized survival.", "claims": [{"id": "claim-method", "statement": "To reduce overfitting, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed with “glmnet” package in R to develop a gene signature.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34194464", "locator": "sections[4] \"Development and Validation of Prognostic Gene Signature\" paragraph 2", "quote": "To reduce overfitting, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed with “glmnet” package in R to develop a gene signature."}], "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 author/s.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34194464", "locator": "sections[18] \"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 author/s."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "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:34194464"], "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": "blocked", "blocked_on": "data:accession_absent", "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": [], "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": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34194464", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fgene.2021.613890", "sha256": "sha256:a5091a4aa030e776ecec6c3a4fa63e9d9b3d3c273529a26879bf32e9b291edb4", "bytes": 38731, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fgene.2021.613890", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8236897", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "asset:table:pmid:34194464:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:78b039a0765a93811a945385cc0247bced9c0b39acd6382a4babd2e1b894c820", "bytes": 1132, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[3]/table-wrap[1]#T1", "version": null, "note": "Clinical characteristics of the hepatocellular carcinoma patients in three independent cohorts.", "structure": {"pmcid": "PMC8236897", "section_index": 3, "section_title": "Datasets", "row_count": 25, "column_count": 4}, "table": {"label": "Table 1", "caption": "Clinical characteristics of the hepatocellular carcinoma patients in three independent cohorts.", "rows": [["Characteristics", "TCGA cohort", "ICGC cohort", "GSE14520 cohort"], ["", "(n = 343)", "(n = 229)", "(n = 221)"], ["Age"], ["<60y", "157 (45.8)", "44 (19.2)", "178 (80.5)"], ["≥60y", "186 (54.2)", "185 (80.8)", "43 (19.5)"], ["Gender"], ["Male", "233 (67.9)", "168 (73.4)", "191 (86.4)"], ["Female", "110 (32.1)", "61 (26.6)", "30 (13.6)"], ["TNM stage"], ["I", "166 (48.4)", "36 (15.7)", "93 (42.1)"], ["II", "80 (23.3)", "105 (45.9)", "77 (34.8)"], ["III", "94 (27.4)", "69 (30.1)", "49 (22.2)"], ["IV", "3 (0.9)", "19 (8.3)", "0"], ["Histologic grade"], ["1", "53 (15.5)", "NA", "NA"], ["2", "165 (48.1)", "NA", "NA"], ["3", "113 (32.9)", "NA", "NA"], ["4", "12 (3.5)", "NA", "NA"], ["AFP"], ["≤ 300 ng/ml", "198 (57.7)", "NA", "119 (53.8)"], [">300 ng/ml", "62 (18.1)", "NA", "100 (45.2)"], ["Survival status"], ["OS years (median)", "4.83", "2.14", "4.35"], ["Alive", "220 (64.1)", "189 (82.5)", "136 (61.5)"], ["Dead", "123 (35.9)", "40 (17.5)", "85 (38.5)"]], "row_count": 25, "column_count": 4, "numeric_cells": 53, "header_rows": 2, "locator": "section[3]/table-wrap[1]#T1"}}, {"id": "asset:table:pmid:34194464:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:004ff67926b921c27ebc6e2d6be555e30778a899f9ae32de3415676088cd7f65", "bytes": 1840, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[16]/table-wrap[1]#T2", "version": null, "note": "The function and mechanism of 8 hypoxia-related genes (HRGs) in hepatocellular carcinoma (HCC).", "structure": {"pmcid": "PMC8236897", "section_index": 16, "section_title": "Discussion", "row_count": 9, "column_count": 5}, "table": {"label": "Table 2", "caption": "The function and mechanism of 8 hypoxia-related genes (HRGs) in hepatocellular carcinoma (HCC).", "rows": [["HRGs", "Full name", "Description", "Mechanism", "References"], ["ENO1", "Enolase 1", "A key glycolytic enzyme", "Promote survival of cancer cells in the hypoxia area by the modulating glycolytic metabolism", "Yu et al., 2018"], ["GPC3", "Glypican 3", "A cell surface heparan sulfate proteoglycan", "Enhance HCC cell migration via upregulating expression and interacting with epithelial-mesenchymal transition -associated targets", "Meng et al., 2021"], ["JMJD6", "Jumonji domain containing 6", "A histone arginine demethylase or lysyloxidase to target histones", "Influence the overall survival in HCC by modulating RNA splicing", "Wan et al., 2019"], ["PGM1", "Phosphoglucomutase 1", "An evolutionary conserved enzyme of the ubiquitous and ancient α-D-phosphohexomutases", "Hinder the glycogen synthesis pathway of tumor cells and promote proliferation and the malignant progression of HCC", "Jin et al., 2018"], ["PYGM", "Muscle glycogen phosphorylase", "An important enzyme in the first step of glycogenolysis", "Have impact on the survival of cancer with low expression in tumor cells", "Favaro et al., 2012"], ["SERPINE1", "Serpin peptidase inhibitor type 1", "A fibrinolysis-related indicator", "Lead to the thrombosis and consequent inhibition of fibrinolysis through a HIF-induced method", "Sanagawa et al., 2016"], ["SLC2A1", "Solute carrier family 2 member 1", "Facilitative glucose transporter", "Provide the primary motivation for the metabolism reprograming", "Nagarajan et al., 2017"], ["STC2", "Stanniocalcin 2", "A human glycoprotein hormone", "Responsible for the balance of calcium and phosphorus", "Wang et al., 2019"]], "row_count": 9, "column_count": 5, "numeric_cells": 15, "header_rows": 1, "locator": "section[16]/table-wrap[1]#T2"}}], "gaps": []}, "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": "To reduce overfitting, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed with “glmnet” package in R to develop a gene signature."}}, {"id": "method-2", "family": "group_comparison", "specific": "wilcoxon", "label": "Group comparison", "dsl_operations": [], "missing_operations": ["group_comparison_wilcoxon"], "expressible": false, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 0.8, "band": "high", "quote": "Wilcoxon"}}, {"id": "method-3", "family": "survival_analysis", "specific": "log_rank_test", "label": "Survival analysis", "dsl_operations": ["logrank_test"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.7, "band": "medium", "quote": "log-rank"}}], "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": "blocked", "tier": "R4", "blocking_axis": "data", "blocked_on": "data:accession_absent", "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": "R4", "reachable": false, "accessions": ["GSE14520 (GPL3921"], "resolved_accessions": [], "statements": ["The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s."], "basis": "The paper names GSE14520 (GPL3921, but the accession does not resolve in the repository (no reason recorded), so the data cannot be reached from here. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["cox_ph"], "assets": ["source:pmid:34194464", "asset:table:pmid:34194464:1", "asset:table:pmid:34194464:2"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:None"]}, "gaps": ["data:accession_absent"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:31:43Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 30786, "completion_tokens": 1943, "cached_tokens": 784}}, "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:34194464", "type": "paper", "label": "pmid:34194464"}, {"id": "source:pmid:34194464", "type": "manuscript", "label": "PMID 34194464 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:34194464", "type": "paper", "label": "pmid:34194464"}, {"id": "source:pmid:34194464", "type": "manuscript", "label": "PMID 34194464 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-34194464", "type": "extraction", "used": ["source:pmid:34194464"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-None", "type": "accession_resolution", "used": ["data:geo:None"], "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:34194464", "parent_hash": "sha256:4b1d15d938a9f5fd16eeb7ee35548936b49b1bb7a84afd60eb3f2bd3835ea525", "fork_of": null, "generation": 6}, "gaps": ["execution.not_run", "method.reader_differs_from_extractor", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:obtain_source_data blocked on data:accession_absent"], "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": ["To reduce overfitting, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed with “glmnet” package in R to develop a gene signature."], "order_basis": "analysis_only", "id": "assay:1"}]}