Background: Trastuzumab has been prevailingly accepted as a beneficial treatment for gastric cancer (GC) by targeting human epidermal growth factor receptor 2 (HER2)-positive. However, the therapeutic resistance of trastuzumab remains a major obstacle, restricting the therapeutic efficacy. Therefore, identifying potential key genes and pathways is crucial to maximize the overall clinical benefits.
Methods: The gene expression profile GSE77346 was retrieved to identify the differentially expressed genes (DEGs) associated with the trastuzumab resistance in GC. Next, the DEGs were annotated by the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The DEGs-coded protein-protein interaction (PPI) networks and the prognostic values of the 20 hub genes were determined. Correlation of the hub genes were analyzed in The Cancer Genome Atlas. The prognostic values of hub genes were further validated by Kaplan-Meier (KM) plotter.
Results: A total of 849 DEGs were identified, with 374 in upregulation and 475 in downregulation. Epithelium development was the most significantly enriched term in biological processes while membrane-bounded vesicle was in cellular compartments and cell adhesion molecular binding was in molecular functions. Pathways in cancer and ECM-receptor interaction were the most significantly enriched for all DEGs. Among the PPI networks, 20 hub genes were defined, including CD44 molecule (CD44), HER-2, and cadherin 1 (CDH1). Six hub genes were associated with favorable OS while eight were associated with poor OS. Mechanistically, 2'-5'-oligoadenylate synthetase 1, 3 (OAS1, OAS3) and CDH1 featured high degrees and strong correlations with other hub genes.
Conclusions: This bioinformatics analysis identified key genes and pathways for potential targets and survival predictors for trastuzumab treatment in GC.
Keywords: Differentially expressed genes; Gastric cancer; Gene ontology; KEGG pathway; Protein-protein interaction; Resistance; Trastuzumab.