MTHFR polymorphism is associated with increased adverse events and poor clinical outcomes in gastric cancer patients with adjuvant S-1 chemotherapy.

S-1, an oral fluoropyrimidine composed of tegafur (a prodrug of 5-fluorouracil), gimeracil and oteracil, is widely used for gastric cancer. However, data on genetic variants influencing S-1 metabolism and their clinical impact remain limited. We enrolled 334 patients who underwent gastrectomy between July 2007 and May 2013, followed by adjuvant S-1 therapy. Genotyping of 46 SNPs in six genes (MTHFR, DPD, OPRT, TS, CYP2A6, TP) was performed to investigate their association with AEs and outcomes. MTHFR rs1801133 C > T was associated with higher hematologic AEs in recessive model (OR = 3.00, p = 0.006), and wild-type haplotype (ht2) was associated with fewer hematologic AEs in dominant model (OR = 0.34, p = 0.003). TP rs470119 G > A was associated with increased non-hematologic AEs in recessive model (OR = 3.42, p = 0.045). Overall AEs were reduced with ht2 of MTHFR in recessive model (OR = 0.43, p = 0.042). With a median follow-up of 93.2 months, MTHFR rs1801133 C > T and CYP2A6 rs28399468 G > T correlated with shorter disease-free survival in dominant model (HR = 2.02, p = 0.014; HR = 1.93, p = 0.046; respectively). MTHFR rs1801133 C > T was associated with worse overall survival in dominant model (HR = 1.95, p = 0.023). Overall, MTHFR rs1801133 C > T was associated with increased hematologic AEs and poorer survival, suggesting its potential relevance as a candidate biomarker in the context of adjuvant S-1 therapy.