https://orcid.org/0009-0009-9269-6845
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Abstract
Background
Neutrophil extracellular traps (NETs) released by neutrophils are crucial for cancer development, metastasis, and can indicate gastric cancer (GC) patients’ prognosis. This study reveals the relevance of NETs-related genes to GC through transcriptome analysis.
Methods
We obtained transcriptome sequencing data of GC from UCSC Xena and screened prognostic NETs-related genes by GEPIA2 database. The signature for NETs was subsequently created using the LASSO–Cox regression. The clinical value of model was further explored using the nomogram and was externally validated by the GEO database. After that, we employed GO, KEGG, and GSEA enrichment analyses to evaluate the bio-functional enrichment and related pathways. Additionally, ESTIMATE, MCP counter, and ssGSEA scores were used to investigate the immunological microenvironment of GC patients. Finally, in the external cohort, neutrophil elastase (NE)-DNA complexes were measured by ELISA, and the prognostic value of NE-DNA in GC was investigated using Cox analysis.
Results
Seven NETs-associated genes (PDE4B, CD93, CTSG, IL6, ELANE, KCNJ15, and CRISPLD2) were filtered to establish the signature and participated in building the nomogram. In comparison to the high-risk group, the overall survival (OS) was much longer in the low-risk group (P=0.005). The validation cohort demonstrated the acceptable predictive ability of the nomogram. The signature was enriched in biological features such as extracellular matrix organization, epithelial-mesenchymal transition and inflammatory response. Moreover, there were substantial differences in immune cell infiltration across the different risk groups (p<0.001), especially the high-risk group having more immune cells that are engaged in the antigen presentation process and associated functions. Finally, in the external cohort, NE-DNA levels were shown to be an independent factor affecting OS prognosis (p=0.006).
Conclusion
Overall, this research identified a novel signature based on seven NETs-associated genes to predict prognosis and identify tumor microenvironment of GC. And high NE-DNA level may be a critical factor in the poor OS associated with NETs.
Abbreviations
NETs, Neutrophil extracellular traps; GC, Gastric cancer; HNSCC, Head and neck squamous cell carcinoma; COAD, Colon adenocarcinoma; KIRC, Kidney renal clear cell carcinoma; OS, Overall survival; PFS, Progression-free survival; TME, Tumor microenvironment; PB, Peripheral blood; TANs, Tumor-associated neutrophils; MPO, Myeloperoxidase; ELANE/NE, Neutrophil elastase; H3Cit, Circulating histone H3; MMP-9, Matrix metalloproteinase 9; TCGA, the Cancer Genome Atlas; GEO, Gene Expression Omnibus; C-index, Concordance index; ROC, Receiver operating characteristic; DEGs, Differentially expressed genes; CI, Confidence interval; DCA, Decision curve analysis; CAF, Cancer-associated fibroblasts; EMT, Epithelial-mesenchymal transition.
Data Sharing Statement
Most of the datasets generated and analyzed during the current study are publicly available data from UCSC Xena (https://xena.ucsc.edu/) and GEO databases (https://www.ncbi.nlm.nih.gov/geo/, ID: GSE62254). And the external validation data during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Publication
This study was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (Quick-PJ2022-03-34). And the study was conducted in accordance with the guidelines of the Declaration of Helsinki. Informed consent was obtained from study participants prior to study initiation. All authors have provided their consent for publication.
Acknowledgments
We thank the TCGA and GEO databases for permitting the authors to use the data.
Disclosure
Ziting Qu, Yanxun Han, and Qingbo Zhu are co-first authors for this study. Kangsheng Gu and Yiyin Zhang are co-correspondence authors for this study. The authors declare that they have no competing interests in this work.