Objective To analyze the gene mutation profile of Chinese patients with gastric cancer and to explore its correlations with clinicopathological characteristics and prognosis.

Methods Fifty-five patients with gastric cancer were enrolled. Next-generation sequencing was performed to detect mutations in cancer-related genes, microsatellite instability, and tumor mutational burden. The associations of high-frequency mutated genes with clinicopathological features and progression-free survival (PFS) were analyzed. Key findings were validated and ethnic heterogeneity was assessed using The Cancer Genome Atlas stomach adenocarcinoma cohort (n = 436).

Results Somatic mutations were identified in 85.45% (47/55) of patients. The most frequently mutated genes were TP53 (29.09%), ARID1A (16.36%), CDH1 (14.55%), LRP1B (14.55%), and PIK3CA (12.73%). TP53 mutations were associated with T4 stage (P = 0.028) and diffuse-type gastric cancer (P = 0.008). CDH1 mutations were enriched in signet-ring cell carcinoma (P = 0.012) and poorly differentiated tumors (P = 0.006). Pathogenic germline mutations were identified in 20% (11/55) of patients. Univariate survival analysis revealed that CDH1 mutation was an independent poor prognostic factor for PFS (hazard ratio = 3.110, 95% confidence interval: 3.370-20.000). Validation in The Cancer Genome Atlas cohort confirmed that the poor prognostic effect of CDH1 mutation was present only in the Asian subgroup (hazard ratio = 5.00, 95% confidence interval: 2.01-12.43), demonstrating significant ethnic heterogeneity.

Conclusion Chinese patients with gastric cancer exhibit a distinct gene mutation profile, and key gene mutations are closely associated with tumor aggressiveness. This multi-cohort validation study indicates ethnic differences in the prognostic value of genes such as CDH1, highlighting the importance of precision molecular classification in the Chinese population.