Prognostic signature of esophageal adenocarcinoma based on pyroptosis-related genes

Abstract

Background: The role of pyroptosis-related genes (PRGs) in esophageal adenocarcinoma (EAC) remains unknown.

Methods: In this study, the first PRGs prognostic signature (PPS) of EAC was constructed based on the results of multivariate stepwise Cox regression analysis. Based on 1,047 samples of EAC and normal esophagus (NE), differentially expressed PRGs were selected for the establishment of the PPS. The discrimination effect of this PPS was detected by receiver operating characteristic curves, and the prognosis value of this PPS was determined through Cox regression analysis and Kaplan-Meier curves. Net benefits of the EAC patients from the nomogram (constructed based on the PPS and some clinical parameters) were assessed via decision curve analysis. The potential molecular mechanism of the PPS in EAC was explored via gene set enrichment analysis. The ability of PPS to distinguish EAC and NE was evaluated based on the results of summary receiver operating characteristic curves.

Results: The significant prognostic value of PPS can be observed at all of the training cohort, test cohort, and validation cohort, such as its independent risk role in the prognosis of the EAC patients (hazard ratio > 0; 95% CI not including 0). The positive net benefits of the nomogram for the EAC patients can be detected via decision curve analysis, and the potential molecular mechanism of the PPS in EAC is likely related to cell pyroptosis. Last, some of the PRGs (particularly CASP5) included in this PPS specifically support its feasibility for identifying EAC (area under the curves > 0.7).

Conclusions: The construction of this PPS in EAC enhances the present understanding of the relationship between PRGs and EAC, thus representing a novel approach to the clinical identification and management of EAC based on PRGs.

Keywords: Adenocarcinoma of esophagus; Gene expression; Prognosis; Pyroptosis.

Fig. 1

The differerntial expression of 17 pyroptosis-related genes (PRGs) between esophageal adenocarcinoma (EAC) and normal esophagus (NE). SMD, standardized mean difference. *p < 0.05; **p < 0.01; ***p < 0.001

Fig. 2

Time-dependent receiver operating characteristic curves based on the PRGs prognostic signature (PPS). In terms of predicting the 1-year survival probability, the risk score of the prognostic signature is more accurate than any single gene in the signature or clinical parameters. a The capability of PPS and PRGs in predicting prognosis of EAC patients in the training cohort. b The capability of PPS and PRGs in predicting the prognosis of EAC patients in the validation cohort. c The capability of PPS and PRGs in predicting the prognosis of EAC patients in the test cohort. d The capability of PPS and clinical parameters in predicting the prognosis of the EAC patients in the entire TCGA cohort

Fig. 3

Box plots and Kaplan–Meier curves. a The relationship between the prognostic signature and clinical parameters of EAC patients. The p value at the top for each panel is based on the Wilcoxon test. b Kaplan–Meier curves of high- and low-risk groups

Fig. 4.

Identification of prognostic factors. Forest plots for univariate (a) and multivariate (b) Cox regression analyses of high- and low-risk groups in terms of the detection by the PPS and clinical parameters of EAC patients

Fig. 5

Nomogram and its verifications. a Nomogram for predicting prognosis of EAC patients; the red dots represent the clinical features of one EAC patient, and, as predicted, his chances of surviving fewer than 5 years, 3 years, and 1 year were 0.943, 0.61, and 0.159, respectively. b Calibration curve of the nomogram. c Decision curve analysis (DCA) of the nomogram

Fig. 6

GSEA and immune correlation analyses. a The molecular functions where three PRGs may participate. b The high-risk group is enriched in the gene set related to immune response. c The rate of immune cell infiltration between the high-risk group and low-risk group based on the prognostic signature. d The correlation of the risk score with three immune cells; ρ, Spearman’s coefficient

Fig. 7

Forest plots of the expressions of the PRGs. Expression differences in CASP5, CASP8, IL6, and TIRAP between the EAC group and NE group can be observed

Fig. 8

Summary receiver operating characteristic curves evaluating whether the four PRGs can identify esophageal adenocarcinoma