Abstract
Backgrounds
Cuproptosis is the most recently identified copper-dependent cell death form that influences tricarboxylic acid (TCA) cycle. However, the relationship between cuproptosis and clinical prognosis, tumor microenvironment infiltration (TME), and response to immunotherapy remains unclear.
Methods
Single-sample gene-set enrichment analysis (ssGSEA) was employed to construct cuproptosisScore (cpS) and 1378 gastric cancer (GC) patients from five independent public datasets were classified into high- or low-cpS groups according to the median of cpS. Then the impacts of cuproptosis on tumor microenvironment infiltration (TME), biological function, response to immunotherapy, and clinical prognosis of GC were evaluated. RiskScore and nomogram were constructed using Lasso Cox regression algorithm to validate its predictive capability in GC patients.
Results
Compared to patients with high cpS, patients with low cpS exhibited poorer prognosis, higher TNM stage, and stronger stromal activation. Meanwhile, the analysis of response to immunotherapy confirmed patients with high cpS could better benefit from immunotherapy and had a better susceptibility to chemotherapeutic drugs. Then, 9 prognosis-related signatures were collected based on differentially expressed genes (DEGs) of cpS groups. Finally, a riskScore model was constructed using the multivariate Cox (multi-Cox) regression coefficients of prognosis-related signatures and had an excellent capability of predicting 1-, 3-, and 5-year survival in GC patients.
Conclusions
This study revealed the role of curproptosis in TME, response to immunotherapy, and clinical prognosis in GC, which highlighted the significant clinical implications of curproptosis and provided novel ideas for the therapeutic application of cuproptosis in GC.
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Data Availability
All public datasets enrolled in this study could download from GEO database (https://www.ncbi.nlm.nih.gov/geo/) and the UCSC Xena browser (https://xenabrowser.net/datapages/). All data generated or analyzed during this study are included in the supplementary information files of this article.
Abbreviations
- GC:
-
Gastric cancer
- PD-L1:
-
Programmed cell death ligand 1
- CTLA-4:
-
Cytotoxic T lymphocyte antigen 4
- ACT:
-
Adoptive T-cell therapy
- TCA:
-
Tricarboxylic acid
- CRGs:
-
Cuproptosis-related genes
- cpS:
-
CuproptosisScore
- TME:
-
Tumor microenvironment infiltration
- TCGA-STAD:
-
The Cancer Genome Atlas-Stomach Adenocarcinoma
- GTEx:
-
Genotype-Tissue Expression Project
- TPM:
-
Transcripts per kilobase million
- ssGSEA:
-
Single-sample gene-set enrichment analysis
- Uni-Cox:
-
Univariate Cox regression
- Multi-Cox:
-
Multivariate Cox regression
- KM:
-
Kaplan–Meier
- OS:
-
Overall survival
- IC50:
-
Semi-inhibitory concentration
- DEGs:
-
Differentially expressed genes
- ROC:
-
Receiver operating characteristic
- AUC:
-
Area under the curve
- GSVA:
-
Gene set variation analysis
- GSEA:
-
Gene set enrichment analysis
- FDR:
-
False discovery rate
- EMT:
-
Epithelial–mesenchymal transition
- TGFβ:
-
Transforming growth factor-β
- PCA:
-
Principal component analysis
- CNV:
-
Copy number variations
- LCSG:
-
Low-cuprotosisScore group
- HCSG:
-
High-cuproptosisScore group
- HGSG:
-
High-geneScore group
- LGSG:
-
Low-geneScore group
- HRSG:
-
High-riskScore group
- LRSG:
-
Low-riskScore group
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Funding
Supported by Special Project of knowledge Innovation of Wuhan Science and Technology Bureau (Dawning project) (Grant No. KYXM2022007), Wuhan University Zhongnan Hospital difficult disease diagnosis and treatment capacity improvement project (oncology) (Grant No. ZLYNXM202017), the Natural Science Foundation of Hubei Province (No. 2020CFB299), the Fundamental Research Funds for the Central Universities (No. 2042022kf1127), and the Program of Excellent Doctoral (Postdoctoral) of Zhongnan Hospital of Wuhan University (Grant No. ZNYB2019003, Grant No. ZNYB2021012, and Grant No. ZNYB2022003).
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All authors contributed to the study conception and design. HN: collected all public datasets and was responsible for the main analysis, then wrote this original draft. HW and MZ: reviewed and edited this original draft. YN, XC and ZZ: were responsible for prognosis analysis of cpS groups. XH: was responsible for data integration. QZ, PC and JF: were responsible for funding acquisition, supervision of the study. FW: was the lead author of the study and guided selection of analysis. All authors read and approved the final manuscript. All authors read and approved the final manuscript.
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Nie, H., Wang, H., Zhang, M. et al. Comprehensive analysis of cuproptosis-related genes in prognosis, tumor microenvironment infiltration, and immunotherapy response in gastric cancer. J Cancer Res Clin Oncol 149, 5453–5468 (2023). https://doi.org/10.1007/s00432-022-04474-4
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DOI: https://doi.org/10.1007/s00432-022-04474-4