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pmid:34221079

Identification of the HMMR Gene as a Diagnostic and Prognostic Biomarker in Hepatocellular Carcinoma Based on Integrated Bioinformatics Analysis.

Honglan Guo · Qinqiao Fan

Evidence-based complementary and alternative medicine : eCAM · 2021 doi:10.1155/2021/5970085

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title
Identification of the HMMR Gene as a Diagnostic and Prognostic Biomarker in Hepatocellular Carcinoma Based on Integrated Bioinformatics Analysis.
doi
10.1155/2021/5970085
pmid
34221079
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Honglan Guo
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Qinqiao Fan
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Evidence-based complementary and alternative medicine : eCAM
year
2021
abstract
BACKGROUND: We aimed to investigate the expression of the hyaluronan-mediated motility receptor (HMMR) gene in hepatocellular carcinoma (HCC) and nonneoplastic tissues and to investigate the diagnostic and prognostic value of HMMR. METHOD: With the reuse of the publicly available The Cancer Genome Atlas (TCGA) data, 374 HCC patients and 50 nonneoplastic tissues were used to investigate the diagnostic and prognostic values of HMMR genes by receiver operating characteristic (ROC) curve analysis and survival analysis. All patients were divided into low- and high-expression groups based on the median value of HMMR expression level. Univariate and multivariate Cox regression analysis were used to identify prognostic factors. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanism of the HMMR genes involved in HCC. The diagnostic and prognostic values were further validated in an external cohort from the International Cancer Genome Consortium (ICGC). RESULTS: HMMR mRNA expression was significantly elevated in HCC tissues compared with that in normal tissues from both TCGA and the ICGC cohorts (all P values <0.001). Increased HMMR expression was significantly associated with histologic grade, pathological stage, and survival status (all P values <0.05). The area under the ROC curve for HMMR expression in HCC and normal tissues was 0.969 (95% CI: 0.948-0.983) in the TCGA cohort and 0.956 (95% CI: 0.932-0.973) in the ICGC cohort. Patients with high HMMR expression had a poor prognosis than patients with low expression group in both cohorts (all P < 0.001). Univariate and multivariate analysis also showed that HMMR is an independent predictor factor associated with overall survival in both cohorts (all P values <0.001). GSEA showed that genes upregulated in the high-HMMR HCC subgroup were mainly significantly enriched in the cell cycle pathway, pathways in cancer, and P53 signaling pathway. CONCLUSION: HMMR is expressed at high levels in HCC. HMMR overexpression may be an unfavorable prognostic factor for HCC.
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Area under the curve (AUC) values obtained from the receiver operating characteristic (ROC) curve analysis was utilized to assess the diagnostic effectiveness of HMMR in both cohorts. In this study, a TCGA-LIHC cohort consisting of samples of 374 human HCC tissues and 50 nonneoplastic tissues, as well as clinicopathological characteristics of patients, was downloaded from the TCGA (https://portal.gdc.cancer.gov/) database. Furthermore, 240 HCC mRNA expression and 260 cases of patients with clinical data from the International Cancer Genome Consortium (ICGC) database were further downloaded (https://dcc.icgc.org/, LIRI-JP), among which 202 normal samples were from solid tissues and 240 primary HCC patients were included in this study to further validate the results yielded in the TCGA cohort.
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sections[5] "2.3. Statistical Analysis" paragraph 2
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Area under the curve (AUC) values obtained from the receiver operating characteristic (ROC) curve analysis was utilized to assess the diagnostic effectiveness of HMMR in both cohorts.
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sections[3] "2.1. Patients' Data" paragraph 2
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In this study, a TCGA-LIHC cohort consisting of samples of 374 human HCC tissues and 50 nonneoplastic tissues, as well as clinicopathological characteristics of patients, was downloaded from the TCGA (https://portal.gdc.cancer.gov/) database.
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sections[6] "2.4. Validation in an External Cohort" paragraph 2
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Furthermore, 240 HCC mRNA expression and 260 cases of patients with clinical data from the International Cancer Genome Consortium (ICGC) database were further downloaded (https://dcc.icgc.org/, LIRI-JP), among which 202 normal samples were from solid tissues and 240 primary HCC patients were included in this study to further validate the results yielded in the TCGA cohort.
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The datasets used in the present study are available from the TCGA (https://portal.gdc.cancer.gov/repository) database and the International Cancer Genome Consortium (https://dcc.icgc.org/) database.
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The datasets used in the present study are available from the TCGA (https://portal.gdc.cancer.gov/repository) database and the International Cancer Genome Consortium (https://dcc.icgc.org/) database.
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Area under the curve (AUC) values obtained from the receiver operating characteristic (ROC) curve analysis was utilized to assess the diagnostic effectiveness of HMMR in both cohorts. In this study, a TCGA-LIHC cohort consisting of samples of 374 human HCC tissues and 50 nonneoplastic tissues, as well as clinicopathological characteristics of patients, was downloaded from the TCGA (https://portal.gdc.cancer.gov/) database. Furthermore, 240 HCC mRNA expression and 260 cases of patients with clinical data from the International Cancer Genome Consortium (ICGC) database were further downloaded (https://dcc.icgc.org/, LIRI-JP), among which 202 normal samples were from solid tissues and 240 primary HCC patients were included in this study to further validate the results yielded in the TCGA cohort.
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Complete file
{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34221079", "kind": "science-record", "revision": 7, "content_hash": "sha256:78ef0f8f820819afee2e568bf314509674f0069bcd93171542f837d252ab3b0a", "created_at": "2026-11-01T15:41:41Z", "updated_at": "2026-11-01T22:04:07Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Identification of the HMMR Gene as a Diagnostic and Prognostic Biomarker in Hepatocellular Carcinoma Based on Integrated Bioinformatics Analysis.", "doi": "10.1155/2021/5970085", "pmid": "34221079", "authors": ["Honglan Guo", "Qinqiao Fan"], "journal": "Evidence-based complementary and alternative medicine : eCAM", "year": 2021, "abstract": "BACKGROUND: We aimed to investigate the expression of the hyaluronan-mediated motility receptor (HMMR) gene in hepatocellular carcinoma (HCC) and nonneoplastic tissues and to investigate the diagnostic and prognostic value of HMMR.\nMETHOD: With the reuse of the publicly available The Cancer Genome Atlas (TCGA) data, 374 HCC patients and 50 nonneoplastic tissues were used to investigate the diagnostic and prognostic values of HMMR genes by receiver operating characteristic (ROC) curve analysis and survival analysis. All patients were divided into low- and high-expression groups based on the median value of HMMR expression level. Univariate and multivariate Cox regression analysis were used to identify prognostic factors. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanism of the HMMR genes involved in HCC. The diagnostic and prognostic values were further validated in an external cohort from the International Cancer Genome Consortium (ICGC).\nRESULTS: HMMR mRNA expression was significantly elevated in HCC tissues compared with that in normal tissues from both TCGA and the ICGC cohorts (all P values <0.001). Increased HMMR expression was significantly associated with histologic grade, pathological stage, and survival status (all P values <0.05). The area under the ROC curve for HMMR expression in HCC and normal tissues was 0.969 (95% CI: 0.948-0.983) in the TCGA cohort and 0.956 (95% CI: 0.932-0.973) in the ICGC cohort. Patients with high HMMR expression had a poor prognosis than patients with low expression group in both cohorts (all P < 0.001). Univariate and multivariate analysis also showed that HMMR is an independent predictor factor associated with overall survival in both cohorts (all P values <0.001). GSEA showed that genes upregulated in the high-HMMR HCC subgroup were mainly significantly enriched in the cell cycle pathway, pathways in cancer, and P53 signaling pathway.\nCONCLUSION: HMMR is expressed at high levels in HCC. HMMR overexpression may be an unfavorable prognostic factor for HCC.", "claims": [{"id": "claim-method", "statement": "Area under the curve (AUC) values obtained from the receiver operating characteristic (ROC) curve analysis was utilized to assess the diagnostic effectiveness of HMMR in both cohorts. In this study, a TCGA-LIHC cohort consisting of samples of 374 human HCC tissues and 50 nonneoplastic tissues, as well as clinicopathological characteristics of patients, was downloaded from the TCGA (https://portal.gdc.cancer.gov/) database. Furthermore, 240 HCC mRNA expression and 260 cases of patients with clinical data from the International Cancer Genome Consortium (ICGC) database were further downloaded (https://dcc.icgc.org/, LIRI-JP), among which 202 normal samples were from solid tissues and 240 primary HCC patients were included in this study to further validate the results yielded in the TCGA cohort.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34221079", "locator": "sections[5] \"2.3. Statistical Analysis\" paragraph 2", "quote": "Area under the curve (AUC) values obtained from the receiver operating characteristic (ROC) curve analysis was utilized to assess the diagnostic effectiveness of HMMR in both cohorts."}, {"asset": "source:pmid:34221079", "locator": "sections[3] \"2.1. Patients' Data\" paragraph 2", "quote": "In this study, a TCGA-LIHC cohort consisting of samples of 374 human HCC tissues and 50 nonneoplastic tissues, as well as clinicopathological characteristics of patients, was downloaded from the TCGA (https://portal.gdc.cancer.gov/) database."}, {"asset": "source:pmid:34221079", "locator": "sections[6] \"2.4. Validation in an External Cohort\" paragraph 2", "quote": "Furthermore, 240 HCC mRNA expression and 260 cases of patients with clinical data from the International Cancer Genome Consortium (ICGC) database were further downloaded (https://dcc.icgc.org/, LIRI-JP), among which 202 normal samples were from solid tissues and 240 primary HCC patients were included in this study to further validate the results yielded in the TCGA cohort."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets used in the present study are available from the TCGA (https://portal.gdc.cancer.gov/repository) database and the International Cancer Genome Consortium (https://dcc.icgc.org/) database.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34221079", "locator": "sections[15] \"Data Availability\" paragraph 2", "quote": "The datasets used in the present study are available from the TCGA (https://portal.gdc.cancer.gov/repository) database and the International Cancer Genome Consortium (https://dcc.icgc.org/) database."}], "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:34221079"], "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": "blocked", "blocked_on": "method:group_comparison_wilcoxon", "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:run_analysis blocked on method:group_comparison_wilcoxon", "step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34221079", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1155/2021/5970085", "sha256": "sha256:16747079214d89330f14ad520009de265730590a2bee7828e6491c037c479308", "bytes": 25909, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1155/2021/5970085", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8221880", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "asset:table:pmid:34221079:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:48f60eec9d6e38ccff2bb336b2052edce6e68d6716139b3af72b7768f2639fec", "bytes": 945, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[8]/table-wrap[1]#tab1", "version": null, "note": "Logistic regression of HMMR expression associated with clinical pathological characteristics.", "structure": {"pmcid": "PMC8221880", "section_index": 8, "section_title": "3.1. Association between Clinicopathological Parameters and HMMR Expression", "row_count": 10, "column_count": 5}, "table": {"label": "Table 1", "caption": "Logistic regression of HMMR expression associated with clinical pathological characteristics.", "rows": [["Clinical characteristics", "Total (N)", "Odds ratio in HMMR expression", "95% CI", "P"], ["TNM stage (III + IV vs. I + II)", "346", "1.623", "1.001–2.653", "0.051"], ["Grade classification (G2 vs. G1)", "232", "1.635", "0.879–3.115", "0.126"], ["(G3 vs. G1)", "176", "2.881", "1.497–5.685", "0.002"], ["(G4 vs. G1)", "67", "3.789", "1.053–15.750", "0.048"], ["Age (≥ 65 vs. < 65)", "370", "0.681", "0.447–1.033", "0.072"], ["Gender (male vs. female)", "370", "0.884", "0.571–1.365", "0.580"], ["Family history of cancer (yes vs. no)", "319", "0.725", "0.455–1.149", "0.172"], ["Vascular invasion (yes vs. no)", "314", "1.326", "0.832–2.122", "0.235"], ["Survival status (dead vs. alive)", "370", "1.958", "1.272–3.036", "0.002"]], "row_count": 10, "column_count": 5, "numeric_cells": 38, "header_rows": 1, "locator": "section[8]/table-wrap[1]#tab1"}}, {"id": "asset:table:pmid:34221079:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:7a3f3ab8150b9282392881b317b84b037f311294e999b9fa8ccd441bd17344d1", "bytes": 620, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[9]/table-wrap[1]#tab2", "version": null, "note": "Univariate analysis of the relationship between clinical variables of HCC patients and their overall survival.", "structure": {"pmcid": "PMC8221880", "section_index": 9, "section_title": "3.2. Diagnostic and Prognostic Value of HMMR Expression in HCC", "row_count": 8, "column_count": 4}, "table": {"label": "Table 2", "caption": "Univariate analysis of the relationship between clinical variables of HCC patients and their overall survival.", "rows": [["Variables", "HR", "95% CI", "P"], ["Age", "1.021", "1.0024–1.0401", "0.027"], ["Sex", "0.586", "0.3732–0.9232", "0.021"], ["TNM stage", "1.464", "1.1416–1.8792", "0.003"], ["HMMR", "1.137", "1.0653–1.2137", "<0.001"], ["Grade", "1.221", "0.8927–1.6686", "0.212"], ["Vascular invasion", "1.443", "0.9038–2.3047", "0.124"], ["Family history", "1.417", "0.9032–2.2250", "0.130"]], "row_count": 8, "column_count": 4, "numeric_cells": 22, "header_rows": 1, "locator": "section[9]/table-wrap[1]#tab2"}}, {"id": "asset:table:pmid:34221079:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:35eff8d3b8bd4bafd6394787a7d0259819752dbd670954709f1574673ae90e34", "bytes": 469, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[9]/table-wrap[2]#tab3", "version": null, "note": "Multivariate analysis of the relationship between clinical variables of HCC patients and their overall survival.", "structure": {"pmcid": "PMC8221880", "section_index": 9, "section_title": "3.2. Diagnostic and Prognostic Value of HMMR Expression in HCC", "row_count": 5, "column_count": 4}, "table": {"label": "Table 3", "caption": "Multivariate analysis of the relationship between clinical variables of HCC patients and their overall survival.", "rows": [["Variables", "HR", "95% CI", "P"], ["Age", "1.019", "0.9993–1.0398", "0.058"], ["Sex", "0.756", "0.4655–1.2279", "0.258"], ["TNM stage", "1.366", "1.0561–1.7672", "0.017"], ["HMMR", "1.136", "1.0586–1.2194", "<0.001"]], "row_count": 5, "column_count": 4, "numeric_cells": 13, "header_rows": 1, "locator": "section[9]/table-wrap[2]#tab3"}}], "gaps": []}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "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-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": "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": 0.8, "band": "high", "quote": "log-rank"}}, {"id": "method-4", "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-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 curve"}}, {"id": "method-6", "family": null, "specific": null, "label": "Receiver operating characteristic (ROC) curve analysis, using TCGA-LIHC and International Cancer Genome Consortium (ICGC) data", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "reordered", "quote": "Area under the curve (AUC) values obtained from the receiver operating characteristic (ROC) curve analysis was utilized to assess the diagnostic effectiveness of HMMR in both cohorts. In this study, a TCGA-LIHC cohort consisting of samples of 374 human HCC tissues and 50 nonneoplastic tissues, as well as clinicopathological characteristics of patients, was downloaded from the TCGA (https://portal.gdc.cancer.gov/) database. Furthermore, 240 HCC mRNA expression and 260 cases of patients with clinical data from the International Cancer Genome Consortium (ICGC) database were further downloaded (https://dcc.icgc.org/, LIRI-JP), among which 202 normal samples were from solid tissues and 240 primary HCC patients were included in this study to further validate the results yielded in the TCGA cohort."}}], "targets": [], "gaps": ["method.reader_named_unmapped", "method.group_comparison_wilcoxon"]}, "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": false, "required_operations": [], "missing_operations": ["group_comparison_wilcoxon"], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: wilcoxon."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. 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