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<p>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 (<i>MTHFR</i>, <i>DPD</i>, <i>OPRT</i>, <i>TS</i>, <i>CYP2A6</i>, <i>TP</i>) was performed to investigate their association with AEs and outcomes. <i>MTHFR</i> rs1801133 C &gt; T was associated with higher hematologic AEs in recessive model (OR = 3.00, <i>p</i> = 0.006), and wild-type haplotype (ht2) was associated with fewer hematologic AEs in dominant model (OR = 0.34, <i>p</i> = 0.003). <i>TP</i> rs470119 G &gt; A was associated with increased non-hematologic AEs in recessive model (OR = 3.42, <i>p</i> = 0.045). Overall AEs were reduced with ht2 of <i>MTHFR</i> in recessive model (OR = 0.43, <i>p</i> = 0.042). With a median follow-up of 93.2 months, <i>MTHFR</i> rs1801133 C &gt; T and <i>CYP2A6</i> rs28399468 G &gt; T correlated with shorter disease-free survival in dominant model (HR = 2.02, <i>p</i> = 0.014; HR = 1.93, <i>p</i> = 0.046; respectively). <i>MTHFR</i> rs1801133 C &gt; T was associated with worse overall survival in dominant model (HR = 1.95, <i>p</i> = 0.023). Overall, <i>MTHFR</i> rs1801133 C &gt; 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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年3月18日

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  • Minsu Kang,
  • Jin Won Kim,
  • Ju Hyun Lee,
  • Lyoung Hyo Kim,
  • Woochan Park,
  • So Hyun Kang,
  • Young Suk Park,
  • Ji-Won Kim,
  • Hyeon Jeong Oh,
  • Sang-Hoon Ahn,
  • Yun-Suhk Suh,
  • Do Joong Park,
  • Hye Seung Lee,
  • Hyung-Ho Kim,
  • Keun-Wook Lee

摘要

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.