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pmid:33748188

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma.

Zhihua Zuo · Junjun Xiong · Chuyi Zeng · Yao Jiang · Kang Xiong · Hualin Tao · Yongcan Guo

Frontiers in molecular biosciences · 2021 doi:10.3389/fmolb.2021.625470

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Experiment

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Data

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title
Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma.
doi
10.3389/fmolb.2021.625470
pmid
33748188
authors array · 7 items
[0]
Zhihua Zuo
[1]
Junjun Xiong
[2]
Chuyi Zeng
[3]
Yao Jiang
[4]
Kang Xiong
[5]
Hualin Tao
[6]
Yongcan Guo
journal
Frontiers in molecular biosciences
year
2021
abstract
Background: Cervical squamous cell carcinoma (CESC) is one of the most frequent malignancies in women worldwide. The level of immune cell infiltration and immune-related genes (IRGs) can significantly affect the prognosis and immunotherapy of CESC patients. Thus, this study aimed to identify an immune-related prognostic signature for CESC. Methods: TCGA-CESC cohorts, obtained from TCGA database, were divided into the training group and testing group; while GSE44001 dataset from GEO database was viewed as external validation group. ESTIMATE algorithm was applied to evaluate the infiltration levels of immune cells of CESC patients. IRGs were screened out through weighted gene co-expression network analysis (WGCNA). A multi-gene prognostic signature based on IRGs was constructed using LASSO penalized Cox proportional hazards regression, which was validated through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. The abundance of immune cells was calculated using ssGSEA algorithm in the ImmuCellAI database, and the response to immunotherapy was evaluated using immunophenoscore (IPS) analysis and the TIDE algorithm. Results: In TCGA-CESC cohorts, higher levels of immune cell infiltration were closely associated with better prognoses. Moreover, a prognostic signature was constructed using three IRGs. Based on this given signature, Kaplan-Meier analysis suggested the significant differences in overall survival (OS) and the ROC analysis demonstrated its robust predictive potential for CESC prognosis, further confirmed by internal and external validation. Additionally, multivariate Cox analysis revealed that the three IRGs signature served as an independent prognostic factor for CESC. In the three-IRGs signature low-risk group, the infiltrating immune cells (B cells, CD4/8 + T cells, cytotoxic T cells, macrophages and so on) were much more abundant than that in high-risk group. Ultimately, IPS and TIDE analyses showed that low-risk CESC patients appeared to present with a better response to immunotherapy and a better prognosis than high-risk patients. Conclusion: The present prognostic signature based on three IRGs (CD3E, CD3D, LCK) was not only reliable for survival prediction but efficient to predict the clinical response to immunotherapy for CESC patients, which might assist in guiding more precise individual treatment in the future.
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Moreover, the survival curve was determined using the Kaplan–Meier method in the R survminer package, where the differences between low- and high-risk groups were calculated by the log-rank test.
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sections[8] "Development and Validation of the Prognostic Signature" paragraph 2
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Moreover, the survival curve was determined using the Kaplan–Meier method in the R survminer package, where the differences between low- and high-risk groups were calculated by the log-rank test.
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Publicly available datasets were analyzed in this study. These data can be found here: TCGA: https://portal.gdc.cancer.gov/; GEO: https://www.ncbi.nlm.nih.gov/geo/.
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sections[21] "Data Availability Statement" paragraph 2
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Publicly available datasets were analyzed in this study. These data can be found here: TCGA: https://portal.gdc.cancer.gov/; GEO: https://www.ncbi.nlm.nih.gov/geo/.
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Genetic profiling to predict recurrence of early cervical cancer
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Development and Validation of the Prognostic Signature
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Clinical variables in the training and testing sets.
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Identification of 20 immune-related prognostic genes by univariate Cox regression analysis. HR, hazard ratio; CI, Confidence interval.
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Identification of 20 immune-related prognostic genes by univariate Cox regression analysis. HR, hazard ratio; CI, Confidence interval.
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0.733 (0.587–0.917)
[3]
7.41
[4]
0.00649
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[0]
TRAC
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−0.235
[2]
0.791 (0.666–0.939)
[3]
7.2
[4]
0.00728
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IGKC
[1]
−0.138
[2]
0.871 (0.787–0.965)
[3]
6.98
[4]
0.00824
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[0]
IL10RA
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−0.259
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0.772 (0.631–0.945)
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6.29
[4]
0.0121
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CD79A
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−0.157
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0.855 (0.749–0.975)
[3]
5.43
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0.0197
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CCL5
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−0.191
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0.826 (0.703–0.972)
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5.28
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0.0216
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ITGB2
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−0.243
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0.785 (0.634–0.972)
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4.95
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0.0261
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CD48
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−0.194
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0.824 (0.694–0.978)
[3]
4.91
[4]
0.0266
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TNFSF13B
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−0.222
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0.801 (0.655–0.979)
[3]
4.68
[4]
0.0305
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CCR5
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−0.055
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0.946 (0.9–0.996)
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4.56
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0.0328
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−0.203
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0.816 (0.674–0.988)
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4.34
[4]
0.0371
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[0]
CD86
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−0.192
[2]
0.825 (0.687–0.992)
[3]
4.19
[4]
0.0405
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[0]
PTPRC
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−0.107
[2]
0.898 (0.81–0.997)
[3]
4.08
[4]
0.0434
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[0]
ITGAL
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−0.169
[2]
0.845 (0.716–0.997)
[3]
3.99
[4]
0.0458
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[0]
CD8A
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−0.157
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0.855 (0.733–0.997)
[3]
3.98
[4]
0.0461
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[0]
FCER1G
[1]
−0.101
[2]
0.904 (0.818–0.999)
[3]
3.94
[4]
0.0473
locator
section[16]/table-wrap[1]#T2
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null
note
Univariable and multivariable Cox regression analyses of clinical characteristics.
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16
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Establishment and Validation of the Prognostic Signature
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6
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7
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TABLE 3
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Univariable and multivariable Cox regression analyses of clinical characteristics.
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95% CI for HR
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95% CI for HR
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[0]
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1.02
[2]
0.998–1.03
[3]
0.084
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1.01
[5]
0.99–1.03
[6]
0.245
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FIGO stage
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1.49
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1.2–1.85
[3]
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[4]
1.38
[5]
1.11–1.72
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0.004
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1.01
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0.8–1.28
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0.927
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[5]
—
[6]
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2.44
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1.49–3.99
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2.24
[5]
1.36–3.68
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0.002
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section[16]/table-wrap[2]#T3
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asset:data:geo:GSE44001 not downloaded
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asset:data:geo:GSE44001 licence not read
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survival_analysis
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Moreover, the survival curve was determined using the Kaplan–Meier method in the R survminer package, where the differences between low- and high-risk groups were calculated by the log-rank test.
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welch_t
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survival_analysis
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Survival analysis
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time_to_event_with_censoring
evidence object · 3 fields
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Kaplan-Meier
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method-4
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survival_analysis
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time_to_event_with_censoring
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Cox proportional hazards
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clustering
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0.8
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method-6
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diagnostic_evaluation
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confusion_counts
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reference_standard_and_test
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0.7
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ROC analysis
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method-7
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contingency_analysis
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Categorical (contingency table) analysis
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meta_analysis
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gwas
candidate
Automated Assays Laravel application and simulated adapters
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readiness object · 8 fields
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complete
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nothing:replicable_now
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logrank_test
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basis
The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: log_rank_test.
capability object · 4 fields
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 object · 6 fields
tier
R1
reachable
true
accessions array · 1 item
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GSE44001
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GSE44001
statements array · 1 item
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Publicly available datasets were analyzed in this study. These data can be found here: TCGA: https://portal.gdc.cancer.gov/; GEO: https://www.ncbi.nlm.nih.gov/geo/.
basis
The paper names GSE44001 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read.
can_run object · 3 fields
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logrank_test
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source:pmid:33748188
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data:geo:GSE44001
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asset:table:pmid:33748188:2
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run_analysis
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MiniMax-M3.1-Flash
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minimax
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minimax
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single_reader
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verbatim
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extraction
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review.human_critique
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pmid:33748188
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data:geo:GSE44001
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GEO GSE44001
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pmid:33748188
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source:pmid:33748188
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PMID 33748188 full text
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data:geo:GSE44001
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GEO GSE44001
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agent:corpus-assay-engine
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agent:minimax-reader
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agent:corpus-assay-engine
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Moreover, the survival curve was determined using the Kaplan–Meier method in the R survminer package, where the differences between low- and high-risk groups were calculated by the log-rank test.
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{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33748188", "kind": "science-record", "revision": 7, "content_hash": "sha256:bdba81ae88d8ac307a8ea8056c4c722467e207cfb00bbc3e15729ef8ea179cb0", "created_at": "2026-11-01T15:41:29Z", "updated_at": "2026-11-01T22:03:22Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma.", "doi": "10.3389/fmolb.2021.625470", "pmid": "33748188", "authors": ["Zhihua Zuo", "Junjun Xiong", "Chuyi Zeng", "Yao Jiang", "Kang Xiong", "Hualin Tao", "Yongcan Guo"], "journal": "Frontiers in molecular biosciences", "year": 2021, "abstract": "Background: Cervical squamous cell carcinoma (CESC) is one of the most frequent malignancies in women worldwide. The level of immune cell infiltration and immune-related genes (IRGs) can significantly affect the prognosis and immunotherapy of CESC patients. Thus, this study aimed to identify an immune-related prognostic signature for CESC. Methods: TCGA-CESC cohorts, obtained from TCGA database, were divided into the training group and testing group; while GSE44001 dataset from GEO database was viewed as external validation group. ESTIMATE algorithm was applied to evaluate the infiltration levels of immune cells of CESC patients. IRGs were screened out through weighted gene co-expression network analysis (WGCNA). A multi-gene prognostic signature based on IRGs was constructed using LASSO penalized Cox proportional hazards regression, which was validated through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. The abundance of immune cells was calculated using ssGSEA algorithm in the ImmuCellAI database, and the response to immunotherapy was evaluated using immunophenoscore (IPS) analysis and the TIDE algorithm. Results: In TCGA-CESC cohorts, higher levels of immune cell infiltration were closely associated with better prognoses. Moreover, a prognostic signature was constructed using three IRGs. Based on this given signature, Kaplan-Meier analysis suggested the significant differences in overall survival (OS) and the ROC analysis demonstrated its robust predictive potential for CESC prognosis, further confirmed by internal and external validation. Additionally, multivariate Cox analysis revealed that the three IRGs signature served as an independent prognostic factor for CESC. In the three-IRGs signature low-risk group, the infiltrating immune cells (B cells, CD4/8 + T cells, cytotoxic T cells, macrophages and so on) were much more abundant than that in high-risk group. Ultimately, IPS and TIDE analyses showed that low-risk CESC patients appeared to present with a better response to immunotherapy and a better prognosis than high-risk patients. Conclusion: The present prognostic signature based on three IRGs (CD3E, CD3D, LCK) was not only reliable for survival prediction but efficient to predict the clinical response to immunotherapy for CESC patients, which might assist in guiding more precise individual treatment in the future.", "claims": [{"id": "claim-method", "statement": "Moreover, the survival curve was determined using the Kaplan–Meier method in the R survminer package, where the differences between low- and high-risk groups were calculated by the log-rank test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33748188", "locator": "sections[8] \"Development and Validation of the Prognostic Signature\" paragraph 2", "quote": "Moreover, the survival curve was determined using the Kaplan–Meier method in the R survminer package, where the differences between low- and high-risk groups were calculated by the log-rank test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Publicly available datasets were analyzed in this study. These data can be found here: TCGA: https://portal.gdc.cancer.gov/; GEO: https://www.ncbi.nlm.nih.gov/geo/.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33748188", "locator": "sections[21] \"Data Availability Statement\" paragraph 2", "quote": "Publicly available datasets were analyzed in this study. 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This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE44001"], "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:GSE44001"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33748188", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fmolb.2021.625470", "sha256": "sha256:63662b7735f6a84f2eca9f5402c9de832b7638691b8626ee8b974da3fe83e535", "bytes": 42154, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fmolb.2021.625470", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC7967036", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE44001", "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=GSE44001", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE44001", "version": null, "note": "Publicly available datasets were analyzed in this study. These data can be found here: TCGA: https://portal.gdc.cancer.gov/; GEO: https://www.ncbi.nlm.nih.gov/geo/.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Publicly available datasets were analyzed in this study. 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