Abstract
Gastric cancer is a highly malignant tumor with poor survival rate. Ferroptosis, a newly defined regulated cell death, is closely related to several tumors. Introduction of ferroptosis is promising for cancer treatments. However, the predictive role of ferroptosis in GC remains elusive. In this study, we screened the ferroptosis-related genes which were differentially expressed between normal and GC tissues. Then, based on these differentially expressed genes (DEGs), the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regressions were applied to construct the 10-gene prognostic signature (SP1, MYB, ALDH3A2, KEAP1, AIFM2, ITGB4, TGFBR1, MAP1LC3B, NOX4, and ZFP36) in TCGA training dataset. Based on the median risk score, all GC patients in TCGA training dataset and GSE84437 testing dataset were classified into a high- or low-risk group. GC patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (P < 0.001). Combined with the clinical characteristics, the risk score was proven as an independent factor for predicting the OS of GC patients. Besides, the GC patients in the high- or low-risk group showed significantly different GO and KEGG functional enrichments, somatic mutation, fractions of immune cells, and immunotherapy response. Then, the expression levels of these genes in signature were further verified in the GC cell lines and our own GC samples (30-paired tumor/normal tissues). Furthermore, the effects of ferroptosis inducer Erastin on these 10 ferroptosis-related genes in GC cell lines were also explored in our study. In conclusion, our study constructed a prognostic signature of 10 ferroptosis-related genes, which could well predict the prognosis and immunotherapy for GC patients.
Highlights
Gastric cancer (GC) is one of the most common malignant tumors in the world, ranking fifth for incidence (1,089,103 cases) and fourth for mortality (768,793 cases) globally in 2020 [1]
According to the value of coefficients and hazard ratio (HR), the genes TGFBR1, MAP1LC3B, NOX4, and ZFP36 were considered as the risk genes, while the genes SP1, MYB, ALDH3A2, KEAP1, AIFM2, and ITGB4 as the protective genes
The results showed that mast cells resting, B cells naive, dendritic cells resting, and monocytes were downregulated in the low-risk groups, while NK cells resting, macrophages M0, and T cells follicular helper were significantly upregulated (P < 0:05, Figures 7(a)–7(c))
Summary
Gastric cancer (GC) is one of the most common malignant tumors in the world, ranking fifth for incidence (1,089,103 cases) and fourth for mortality (768,793 cases) globally in 2020 [1]. The incidence rate of GC is the highest in digestive malignant tumors in China [2]. Due to the comprehensive treatments in the last few decades, including curative surgery, chemoradiotherapy, targeted therapy, and immunotherapy, the prognosis of GC patients has improved a lot. Most patients are diagnosed at advanced stages; the overall survival (OS) rate of 5 years remains less than 40% [3]. It is necessary to identify novel and reliable biomarkers to accurately predict prognosis, to find potential therapeutic targets, and to improve the outcomes of GC patients
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