Integration of cuproptosis-related gene signatures in stomach adenocarcinoma: implications for prognostic prediction and therapeutic strategies in cancer drug resistance.

backgroundStomach adenocarcinoma (STAD) is a prevalent and aggressive cancer, often diagnosed at later stages, which poses challenges for effective treatment. Despite advancements in cancer therapies, the phenomenon of tumor drug resistance remains a critical hurdle. Recent studies have highlighted cuproptosis, a copper-dependent regulated cell death process, as a potential mechanism in various cancers, including STAD. This study integrates cuproptosis-related gene signatures with clinical features to better predict prognosis and explore potential therapeutic targets, focusing on the role of cuproptosis in overcoming tumor resistance mechanisms.

methodsUsing comprehensive datasets from TCGA-STAD (n = 375 tumor samples, 32 normal samples), GTEx (n = 211 normal gastric tissues), and GEO (GSE84437 and GSE29272), we analyzed the expression of genes associated with cuproptosis. We examined genetic alterations, immune infiltration, and constructed multivariate Cox regression models with clinicopathological covariates (age, gender, TNM stage, histological grade, residual tumor status) to assess the relationship between cuproptosis gene expression and patient survival outcomes, including overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). Drug sensitivity analysis was performed using the Genomics of Drug Sensitivity in Cancer (GDSC) database.

resultsOur analysis identified significant upregulation of several cuproptosis-related genes, including FDX1, which was correlated with improved prognosis and immune cell infiltration patterns. High expression of FDX1 was associated with better OS and DSS outcomes. Further genetic alterations, notably in CDKN2A, were frequent and linked to poor prognosis, highlighting the complexity of tumor drug resistance in STAD. Prognostic models incorporating FDX1, PDHA1, and LIAS expression stratified patients into distinct risk categories, emphasizing their potential as biomarkers for personalized therapeutic strategies.

conclusionsThis study underscores the importance of cuproptosis-related genes, particularly FDX1, in the prognosis and therapeutic response of STAD. By integrating molecular features with clinical data, we offer insights into the potential for overcoming drug resistance in cancer therapy. These findings lay the groundwork for future research into targeted treatments that modulate cuproptosis, offering a novel approach to tackling tumor progression and resistance in STAD.