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<p>Dihydropyrimidine dehydrogenase (DPD), which is encoded by the <i>DPYD</i> gene, plays an important role in the metabolism of fluoropyrimidine (FP) drugs, including tegafur, in S-1. A decrease in DPD activity can cause severe FP-related toxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for FP and <i>DPYD</i> polymorphisms recommend FP dose adjustments based on the four major <i>DPYD</i> polymorphisms. However, multiple rare variants of <i>DPYD</i> have been reported. We present the case of a man in his 50s with cT3N0M0 tongue squamous cell carcinoma who developed severe myelosuppression and diarrhea after the initiation of S-1 (tegafur/gimeracil/oteracil) despite appropriate dosing. On day 20 of treatment, the patient developed grade 4 neutropenia and septic shock and required ICU admission. Genetic testing identified a rare heterozygous <i>DPYD</i> variant (c. 812delT) that causes a frameshift and a presumed loss of enzyme function, suggesting an underlying cause of the severe adverse events. Although severe toxicity occurred, marked tumor shrinkage allowed for less invasive surgery. This case highlights the need for expanded genetic screening beyond the guideline-listed variants, particularly in Asian populations, where common variants differ. Combining genotypic and phenotypic evaluations of DPD activity may improve the prediction and prevention of FP-related toxicities, supporting safer and more effective use of FP drugs.</p>

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A rare variant in DPYD c.812delT causes severe adverse events of S-1 in a patient with tongue cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Hiroki Ishimura,
  • Atsushi Suehiro,
  • Daiki Hira,
  • Eiji Hishinuma,
  • Midori Kato,
  • Masamitsu Maekawa,
  • Taishi Yasuda,
  • Yurie Katsube,
  • Yoshiki Katada,
  • Natsuki Imayoshi,
  • Yuki Shigetsura,
  • Shunsaku Nakagawa,
  • Masahiro Tsuda,
  • Masahiro Hiratsuka,
  • Tomohiro Terada

摘要

Dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, plays an important role in the metabolism of fluoropyrimidine (FP) drugs, including tegafur, in S-1. A decrease in DPD activity can cause severe FP-related toxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for FP and DPYD polymorphisms recommend FP dose adjustments based on the four major DPYD polymorphisms. However, multiple rare variants of DPYD have been reported. We present the case of a man in his 50s with cT3N0M0 tongue squamous cell carcinoma who developed severe myelosuppression and diarrhea after the initiation of S-1 (tegafur/gimeracil/oteracil) despite appropriate dosing. On day 20 of treatment, the patient developed grade 4 neutropenia and septic shock and required ICU admission. Genetic testing identified a rare heterozygous DPYD variant (c. 812delT) that causes a frameshift and a presumed loss of enzyme function, suggesting an underlying cause of the severe adverse events. Although severe toxicity occurred, marked tumor shrinkage allowed for less invasive surgery. This case highlights the need for expanded genetic screening beyond the guideline-listed variants, particularly in Asian populations, where common variants differ. Combining genotypic and phenotypic evaluations of DPD activity may improve the prediction and prevention of FP-related toxicities, supporting safer and more effective use of FP drugs.