A novel tumor doubling time-related immune gene signature for prognosis prediction in hepatocellular carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34627241", "kind": "science-record", "revision": 5, "content_hash": "sha256:ae8a88cb6b8b8ebd1b609a6b0bf3e71fb21120d29d73d7e7e32d92fc25582453", "created_at": "2026-11-01T17:36:16Z", "updated_at": "2026-11-01T22:47:40Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "A novel tumor doubling time-related immune gene signature for prognosis prediction in hepatocellular carcinoma.", "doi": "10.1186/s12935-021-02227-w", "pmid": "34627241", "authors": ["Genhao Zhang", "Lisa Su", "Xianping Lv", "Qiankun Yang"], "journal": "Cancer cell international", "year": 2021, "abstract": "BACKGROUND: Hepatocellular carcinoma (HCC) has become a global health issue of wide concern due to its high prevalence and poor therapeutic efficacy. Both tumor doubling time (TDT) and immune status are closely related to the prognosis of HCC patients. However, the association between TDT-related genes (TDTRGs) and immune-related genes (IRGs) and the value of their combination in predicting the prognosis of HCC patients remains unclear. The current study aimed to discover reliable biomarkers for anticipating the future prognosis of HCC patients based on the relationship between TDTRGs and IRGs.\nMETHODS: Tumor doubling time-related genes (TDTRGs) were acquired from GSE54236 by using Pearson correlation test and immune-related genes (IRGs) were available from ImmPort. Prognostic TDTRGs and IRGs in TCGA-LIHC dataset were determined to create a prognostic model by the LASSO-Cox regression and stepwise Cox regression analysis. International Cancer Genome Consortium (ICGC) and another cohort of individual clinical samples acted as external validations. Additionally, significant impacts of the signature on HCC immune microenvironment and reaction to immune checkpoint inhibitors were observed.\nRESULTS: Among the 68 overlapping genes identified as TDTRG and IRG, a total of 29 genes had significant prognostic relevance and were further selected by performing a LASSO-Cox regression model based on the minimum value of λ. Subsequently, a prognostic three-gene signature including HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), C-type lectin domain family 1 member B (CLEC1B), and Collectin sub-family member 12 (COLEC12) was finally identified by stepwise Cox proportional modeling. The signature exhibited superior accuracy in forecasting the survival outcomes of HCC patients in TCGA, ICGC and the independent clinical cohorts. Patients in high-risk subgroup had significantly increased levels of immune checkpoint molecules including PD-L1, CD276, CTLA4, CXCR4, IL1A, PD-L2, TGFB1, OX40 and CD137, and are therefore more sensitive to immune checkpoint inhibitors (ICIs) treatment. Finally, we first found that overexpression of CLEC1B inhibited the proliferation and migration ability of HuH7 cells.\nCONCLUSIONS: In summary, the prognostic signature based on TDTRGs and IRGs could effectively help clinicians classify HCC patients for prognosis prediction and individualized immunotherapies.", "claims": [{"id": "claim-method", "statement": "Tumor doubling time-related genes (TDTRGs) were acquired from GSE54236 by using Pearson correlation test and immune-related genes (IRGs) were available from ImmPort. Prognostic TDTRGs and IRGs in TCGA-LIHC dataset were determined to create a prognostic model by the LASSO-Cox regression and stepwise Cox regression analysis.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34627241", "locator": "sections[0] \"Abstract\" paragraph 2", "quote": "Tumor doubling time-related genes (TDTRGs) were acquired from GSE54236 by using Pearson correlation test and immune-related genes (IRGs) were available from ImmPort. Prognostic TDTRGs and IRGs in TCGA-LIHC dataset were determined to create a prognostic model by the LASSO-Cox regression and stepwise Cox regression analysis."}], "state": "complete"}, {"id": "claim-data-access", "statement": "All data generated or analyzed during the present study was downloaded from TCGA database, ICGC database, GEO database, and HPA database. The original CT values of qRT-PCR in the clinical cohort are shown in the Original Data. We can find the datasets analyzed in this study in the https://xena.ucsc.edu and https://dcc.icgc.org/projects/LIRI-JP.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34627241", "locator": "sections[28] \"notes\" paragraph 1", "quote": "All data generated or analyzed during the present study was downloaded from TCGA database, ICGC database, GEO database, and HPA database. The original CT values of qRT-PCR in the clinical cohort are shown in the Original Data. We can find the datasets analyzed in this study in the https://xena.ucsc.edu and https://dcc.icgc.org/projects/LIRI-JP."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Among 68 genes overlapping between tumor doubling time-related genes and immune-related genes, 29 had prognostic relevance, and a prognostic signature comprising HACE1, CLEC1B, and COLEC12 was identified and validated.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:34627241", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Among the 68 overlapping genes identified as TDTRG and IRG, a total of 29 genes had significant prognostic relevance and were further selected by performing a LASSO-Cox regression model based on the minimum value of λ. Subsequently, a prognostic three-gene signature including HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), C-type lectin domain family 1 member B (CLEC1B), and Collectin sub-family member 12 (COLEC12) was finally identified by stepwise Cox proportional modeling."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Among 68 genes overlapping between tumor doubling time-related genes and immune-related genes, 29 had prognostic relevance, and a prognostic signature comprising HACE1, CLEC1B, and COLEC12 was identified and validated.", "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:34627241"], "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:GSE54236"], "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:GSE54236"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34627241", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s12935-021-02227-w", "sha256": "sha256:62a0839f9a7b4bda42bcb39a8e1528ceee3f26e9d015a67bb827c441fc5ac5d5", "bytes": 32041, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s12935-021-02227-w", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8502295", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE54236", "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=GSE54236", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE54236", "version": null, "note": "All data generated or analyzed during the present study was downloaded from TCGA database, ICGC database, GEO database, and HPA database. 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