Risk signature of NETosis-related subtype predicts prognosis and evaluates immunotherapy effectiveness in gastric cancer

Background: Gastric cancer (GC) has a high incidence and mortality rate with a poor prognosis, so it is crucial to search for new biomarkers. The role of NETosis, a newly identified type of programmed cell death, in GC and its underlying mechanisms have yet to be explored and still require thorough investigation. Our research seeks to enhance our comprehension of NETosis and may offer novel approaches for treating GC.

Methods: Utilizing The Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD) dataset for training and the GSE84433 dataset for validation, our study delved into the associations between NETosis-related genes and the clinical risk of GC. Through comprehensive clustering, enrichment, and immune infiltration analyses, we evaluated the prognostic relevance of these NETosis genes in vivo. Furthermore, we devised a NETosis-related risk signature (NRRS) to assess its implications in risk stratification, survival prognosis, immune infiltration, and drug sensitivity. The NRRS's accuracy was validated by immunohistochemical staining.

Results: By applying consensus clustering to data from 62 NETosis-related genes, we categorized patients into two distinct subgroups, C1 and C2. These subgroups demonstrated significant differences. Following this, we developed the NRRS using the least absolute shrinkage and selection operator (LASSO) regression analysis. This process involved the selection of the following genes: CXCR4, NRP1, PDCD1, CTLA4, AKR1B1, SERPINE1, RGS2, SLCO2A1, TNFAIP2, RNASE1, DOC2B, APOD, ENTPD2, and CCL24. High-risk and low-risk groups can be accurately distinguished. We further verify in the verification set. These results suggest that NETosis is related to the microenvironment of GC. Our designed NRRS can predict the survival of patients with GC.

Conclusions: We emphasized the relationship between NETosis and GC. We built and validated the value of NRRS. This contributes to deepening our view of NETosis and potentially provides new strategies for GC treatment.