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Related Experiment Videos

DPYD*2A mutation: the most common mutation associated with DPD deficiency.

M W Saif1, Hany Ezzeldin, Katisha Vance

  • 1Yale University School of Medicine, Section of Medical Oncology, 333 Cedar Street; FMP 116, New Haven, CT 06520, USA. wasif.saif@yale.edu

Cancer Chemotherapy and Pharmacology
|December 14, 2006
PubMed
Summary

Dihydropyrimidine dehydrogenase (DPD) deficiency, identified by DPYD genotyping, can cause severe 5-fluorouracil (5-FU) toxicity. Genetic analysis revealed a common DPYD mutation in a patient experiencing fatal toxicity, highlighting the importance of pharmacogenetic screening.

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Area of Science:

  • Pharmacogenetics
  • Oncology
  • Biochemistry

Background:

  • Dihydropyrimidine dehydrogenase (DPD) is crucial for metabolizing 5-fluorouracil (5-FU), an anticancer drug.
  • DPD deficiency leads to severe, potentially fatal, toxicity from 5-FU, including gastrointestinal, neurological, and hematological adverse events.
  • This pharmacogenetic syndrome is often asymptomatic until exposure to 5-FU.

Observation:

  • A 75-year-old patient with metastatic pancreatic cancer experienced fatal toxicity (grade 4 thrombocytopenia, grade 3 coagulopathy, grade 3 neurotoxicity) after 5-FU administration.
  • Due to pancytopenia, DPD enzyme activity could not be measured directly.
  • Genotypic analysis of the DPYD gene was performed using DHPLC and confirmed by DNA sequencing.

Findings:

  • Genotyping identified a heterozygous IVS14 + 1 G > A mutation in the DPYD gene, known as DPYD*2A.

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  • This mutation is a common cause of DPD deficiency.
  • The IVS14 + 1 G > A mutation results in exon skipping and a 165-bp deletion in DPD mRNA, leading to partial DPD deficiency.

    • Implications:

    • DPYD genotyping, specifically screening for the DPYD*2A mutation, is a valuable tool for identifying patients at risk of severe 5-FU toxicity.
    • This pharmacogenetic approach can guide 5-FU treatment decisions and potentially prevent life-threatening adverse events.
    • Early identification of DPD deficiency through genetic testing is essential for personalized cancer therapy.