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

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Abstract

Background

Dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the elimination of approximately 80% of administered dose of 5-FU. DPD deficiency has been associated with severe 5-FU toxicity. Syndrome of DPD deficiency manifests as diarrhea, stomatitis, mucositis, and neurotoxicity and in some cases death. This is a true pharmacogenetic syndrome, with symptoms being unrecognizable until exposure to the drug.

Patients and methods

A 75-year-old patient with metastatic pancreatic adenocarcinoma developed grade 4 thrombocytopenia, grade 3 coagulopathy, and grade 3 neurologic toxicity with a fatal outcome following administration of 5-FU. Due to pancytopenia, DPD activity could not be determined in peripheral blood mononuclear cells (PBMC) using a previously described radioassay. Therefore, screening and genotypic analysis of homozygous and heterozygous, known and unknown sequence variants, in the DPYD gene were performed using DHPLC as previously described. All DPYD sequence variants identified by DHPLC were confirmed by DNA sequencing using a dideoxynucleotide chain termination method and capillary electrophoresis on an ABI 310 Automated DNA Sequencer.

Results

Genotyping analysis of the DPYD gene revealed the presence of the heterozygous mutation, IVS14 + 1 G > A, DPYD*2A.

Conclusion

Genotypic analysis using DHPLC can be employed to screen DPD deficiency in a patient with severe neutropenia. The mutation IVS14 + 1 G > A, DPYD*2A, is the most common mutation associated with DPD deficiency. A G > A base change at the splice recognition sequence of intron 14, leads to exon skipping and results in a 165-bp deletion in the DPD mRNA. We have previously demonstrated that a homozygote DPYD*2A genotype results in complete deficiency while the heterozygous DPYD*2A genotype results in partial deficiency of DPD.

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Authors and Affiliations

  1. Yale University School of Medicine, Section of Medical Oncology, 333 Cedar Street; FMP 116, New Haven, CT, 06520, USA

    M. W. Saif

  2. University of Alabama at Birmingham (UAB), Birmingham, AL, USA

    Hany Ezzeldin, Katisha Vance, Sandra Sellers & Robert B. Diasio

Authors
  1. M. W. Saif
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  2. Hany Ezzeldin
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  3. Katisha Vance
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  4. Sandra Sellers
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  5. Robert B. Diasio
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Corresponding author

Correspondence to M. W. Saif.

Additional information

This work was supported in part by NIH grant CA 62164.

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Saif, M.W., Ezzeldin, H., Vance, K. et al. DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol 60, 503–507 (2007). https://doi.org/10.1007/s00280-006-0392-5

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  • DOI: https://doi.org/10.1007/s00280-006-0392-5

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