Gene Variations in RNA Modification Pathway Linked to Poor Survival After Gastric Cancer Surgery

Background/Objectives: N6-methyladenosine (m6A) RNA modification is a major epitranscriptomic regulator of mRNA stability and translation. Genetic variants in the m6A pathway may influence gastric cancer progression, but their prognostic significance after curative gastrectomy remains uncertain. Methods: This retrospective study included 226 patients with gastric adenocarcinoma who underwent curative gastrectomy. Single nucleotide polymorphisms in five m6A-related genes (METTL3, METTL14, FTO, ALKBH5, and YTHDF1) were genotyped. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan–Meier and log-rank tests. Multivariable Cox regression was performed after adjustment for age, sex, tumor stage, lymph node status, and adjuvant therapy. Results: During a median follow-up of 38 months, 78 patients (34.5%) died and 92 (40.7%) experienced recurrence. High-risk m6A genotypes were associated with significantly poorer survival. The 5-year OS was 68.2% in the low-risk group versus 41.5% in the high-risk group (p < 0.001), while 5-year DFS was 61.4% versus 36.8% (p < 0.001). High-risk genotypes independently predicted worse OS (HR 1.87, 95% CI 1.28–2.74; p = 0.001) and DFS (HR 1.94, 95% CI 1.36–2.78; p < 0.001). Patients with the highest genetic risk scores had the poorest outcomes, particularly those with stage III–IV disease. Conclusion: Genetic variants in the m6A RNA modification pathway are independently associated with poorer survival after curative gastrectomy and may serve as prognostic biomarkers for risk stratification and personalized management in gastric cancer.