Dihydropyrimidine Dehydrogenase Gene Mutation

Dihydropyrimidine Dehydrogenase Gene Mutation

The DPYD gene codes for dihydropyrimidine dehydrogenase (DPD). DPD is the rate-limiting enzyme in the metabolic pathway that degrades the pyrimidine bases, uracil and thymine. DPD deficiency results in impaired pyrimidine metabolism. This deficiency has autosomal recessive inheritance and is more common among African-Americans than it is among Caucasians. Approximately 8% of the population has at least partial DPD deficiency.

DPD also breaks down pyrimidine-based chemotherapeutic agents such as 5-fluorouracil (5-FU) and capecitabine. More than 80% of these drugs is metabolized by DPD and then excreted. Less than 20% of the administered dose remains to be taken up by cells. Cancer patients with DPD deficiency are exposed to much higher levels of these drugs and can develop severe myelosuppression or life-threatening toxicity. 

The most common DPYD variants that result in no enzyme activity include: 1905+1G>A (*2A), 299_302del (*7), 703C>T (*8), 2983G>T (*10), and 1679T>G (*13). The parentheses indicate the allele on which each nucleotide change occurs. 

The most common DPYD variants that result in reduced activity include: 2846A>T (rs67376798), 1129-5923C>G (rs75017182,, and 557A>G (rs115232898).

These mutations are detected by polymerase chain reaction (PCR) amplification of a portion of the DPYD gene and DNA sequencing.

Specimen requirement is whole blood collected in a lavender-top (EDTA) tube or a saliva-swab collection kit. 

References

Amstutz U, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018;103(2):210-216. 

Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.