A Novel Neutrophil Extracellular Traps Signature for Overall Survival Prediction and Tumor Microenvironment Identification in Gastric Cancer

Ziting Qu; Yanxun Han; Qingbo Zhu; Wenxi Ding; Yuyan Wang; Yan Zhang; Wei Wei; Yu Lei; Min Li; Yang Jiao; Kangsheng Gu; Yiyin Zhang

doi:10.2147/JIR.S417182

A Novel Neutrophil Extracellular Traps Signature for Overall Survival Prediction and Tumor Microenvironment Identification in Gastric Cancer

J Inflamm Res. 2023 Aug 14:16:3419-3436. doi: 10.2147/JIR.S417182. eCollection 2023.

Authors

Ziting Qu^#¹, Yanxun Han^#², Qingbo Zhu^#¹, Wenxi Ding¹, Yuyan Wang¹, Yan Zhang¹, Wei Wei¹, Yu Lei¹, Min Li¹, Yang Jiao¹, Kangsheng Gu^#¹, Yiyin Zhang^#¹

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
² Department of Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.

^# Contributed equally.

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.

Keywords: NETs; gastric cancer; gene signature; prognosis; tumor microenvironment.

Grants and funding

This study was supported by grants from the Natural Science Foundation of Anhui Province (No. 1908085QH333), Key Research and Development Project of Anhui Province (No. 202004j07020044), Foundation of Beijing Life Oasis Public Service Center (No. cphcf-2022-021), and the Natural Science Research Project of Anhui Provincial University (No. KJ2018ZD019).