GALNT14 drives gastric cancer aggressiveness via enzyme-dependent activation of a TGF-β-EMT-β-catenin axis in the post-Helicobacter pylori eradication era

Despite extensive effort to eradicate Helicobacter pylori (HP), gastric cancer (GC) remains a major global health burden. As HP-related carcinogenesis declines, host genetic factors are increasingly important for risk prediction and management in the post-HP eradication era. The GALNT14 -rs9679162 polymorphism, previously linked to gastrointestinal malignancies, may influence GC susceptibility and outcomes, but its pathogenic role remains unclear. A total of 472 subjects undergoing routine gastroscopy were analyzed, including 275 GC patients and 197 controls. Clinicopathological features, HP infection, and GALNT14 -rs9679162 genotypes were assessed. Associations with GC risk and survival were evaluated by logistic and Cox regression. GALNT14 function was examined in tissues and immortalized gastric epithelial cells expressing wild-type or mutant GALNT14. This study was conducted in Taiwan, where anti-HP treatment was covered by national health insurance. As a result, GC patients were associated with lower concurrent HP infection (30.2% vs. 66.5%) ( P < 0.001). The percentage of GALNT14 -rs9679162 “GG” genotype was higher in GC (28.7% vs. 19.8%, P = 0.036) and independently associated with an increased risk (adjusted OR = 1.86, P = 0.040). Among GC patients, the “GG” genotype predicted higher recurrence (35.4% vs. 10.7%) and metastasis (44.3% vs. 24.5%) (both P < 0.01). Additionally, it was associated with poorer overall, recurrence-free, and metastasis-free survival (HR = 2.36–4.16, all P < 0.001). The “GG” genotype was associated with higher tissue expression of GALNT14 and its ectopic expression in immortalized gastric epithelial cells enhanced proliferative, migratory, anchorage-independent, and tumorigenic phenotypes via TGF-β/β-catenin–driven epithelial–mesenchymal transition. GALNT14 -rs9679162 “GG” serves as a prognostic marker and host genetic factor associated with aggressive gastric cancer in the post-HP eradication era, revealing a potential link between germline variation, GALNT14 upregulation, and aggressive gastric epithelial behavior.