ADGRF4 and ADGRL4 as novel prognostic biomarkers and potential therapeutic implications in stomach adenocarcinoma

BACKGROUND: This study explored the differential expression of adhesion G protein-coupled receptor (ADGR) genes in stomach adenocarcinoma (STAD), evaluated their association with STAD prognosis, and explored their potential therapeutic implications. METHODS: The gene expression profiles of STAD and normal gastric tissues were obtained from TCGA and GTEx databases and analyzed using the DEseq2 R package. External validation was performed using three GEO datasets. Co-expression patterns of ADGRF4 and ADGRL4 with immune-related molecules were analyzed using Spearman correlation. The prognostic values of ADGRs were evaluated using multivariate Cox risk models and Kaplan-Meier survival analyses. The tumor microenvironment composition and immune infiltration were analyzed using the ESTIMATE R package and CIBERSORT algorithm. GO and KEGG enrichment analyses were performed using DAVID. Immunohistochemistry was conducted to validate gene expression in 50 pairs of STAD and adjacent normal tissues. Drug sensitivity was analyzed using the oncoPredict R package. RESULTS: ADGRF4 and ADGRL4 were significantly upregulated in STAD tissues and independently associated with poor prognosis and the tumor microenvironment composition. Functional enrichment analysis revealed that ADGRF4 was primarily associated with epithelial development and neuroactive ligand-receptor interaction, whereas ADGRL4 was linked to extracellular matrix organization and calcium signaling pathways. Immunohistochemistry confirmed the significantly higher expression of both proteins in gastric cancer tissues than in normal tissues. External validation using GEO datasets confirmed the upregulation and prognostic significance of ADGRL4. Drug sensitivity analysis indicated that ADGRL4 expression was significantly correlated with sensitivity to the Chk1/Chk2 inhibitor AZD7762. CONCLUSION: ADGRF4 and ADGRL4 were significantly overexpressed in STAD and independently associated with poor prognosis. Expression of these genes was correlated with changes in tumor microenvironment and immune cell infiltration, indicating their potential association in STAD progression. These findings suggest that ADGRF4 and ADGRL4 could serve as novel prognostic biomarkers with potential therapeutic significance in gastric cancer.