An integrated machine learning framework for developing and validating a prognostic risk model of gastric cancer based on endoplasmic reticulum stress-associated genes

Background

Gastric cancer (GC), a prevalent and deadly malignancy, demonstrates poor survival outcomes. Evidence has emerged indicating that disruptions in endoplasmic reticulum homeostasis are significantly implicated in the onset and progression of various oncological conditions. This study was designed to construct a prognostic model based on genes related to endoplasmic reticulum stress(ERS) to predict survival outcomes in patients with GC.

Methods

Expression profiling data for GC samples were extracted and analyzed from TCGA-STAD, revealing 214 genes related to endoplasmic reticulum stress that show differential expression when compared with normal gastric tissue. Building on these insights, a prognostic model was formulated using data from TCGA-STAD and validated through subsequent analyses of GEO datasets. The tumor immune dysfunction and exclusion(TIDE) algorithm was applied to determine the susceptibility of individuals in high- and low-risk categories to immunotherapy. The presence of immune and stromal cells within the tumor microenvironment was assessed with the aid of the ESTIMATE algorithm. Sensitivity variations to prevalent anticancer drugs between the risk groups were evaluated using the Genomics of Drug Sensitivity in Cancer(GDSC) database, and prospective therapeutic agents were confirmed through molecular docking techniques.

Results

Thirty-one endoplasmic reticulum stress (ERS)-related differentially expressed genes (DEGs) crucial for prognosis in GC were pinpointed. These DEGs were then used to construct a prognostic model and were considered as independent prognostic factors for GC patients. This risk model proved to have a good predictive performance for estimating the overall survival of these patients. The patients placed into the high-risk group showed worse results and lower sensitivity to immunotherapy. Moreover, five specific targeted therapy drugs, namely BMS-754807, Dasatinib, JQ1, AZD8055 and SB505124, produced better results in the treatment of the high-risk group of patients.

Conclusions

A new molecular prognostic model associated with ERS was established and validated for GC and showed relatively good discriminative and predictive ability. This model greatly expands the collection of weapons in the armoury of prognostic analysis in GC.