Studies have highlighted a link between the complete or partial loss of DYPD function and clinical responses to 5-FU; however, the underlying molecular basis of DPD deficiency remains poorly understood.
The steady-state concentration of 5-FU administered through the hepatic artery was achieved after 15 h. DPD levels were analysed through determining the ratio of plasma uracil (U) and dihydrouracil (UH2) by HPLC, and the results indicated a mild DPD deficiency in the patients with HCC.
Genome sequencing reveals a novel genetic mechanism underlying dihydropyrimidine dehydrogenase deficiency: A novel missense variant c.1700G>A and a large intragenic inversion in DPYD spanning intron 8 to intron 12.
A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency.
DPYD genotyping for alleles 7, *2A, *13 and Y186C was not helpful in the identification of patients with severe DPD deficiency in this series of patients.
Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care.
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.
Different tests based on assessing DPD enzyme activity, genetic variants in DPYD and mRNA variants have been studied for screening for DPD deficiency, but none of these are implemented broadly into clinical practice.
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome.
However, severe toxicity is a major clinical problem and has been reported in association with deleterious sequence variants in dihydropyrimidine dehydrogenase (DPD) coding-gene (DPYD), causing DPD deficiency.
Analysis of severely affected patients with dihydropyrimidine dehydrogenase deficiency reveals large intragenic rearrangements of DPYD and a de novo interstitial deletion del(1)(p13.3p21.3).
Recently, hypermethylation of the DPYD promoter region has been proposed as an alternative mechanism for DPD deficiency and thus as a major cause of severe 5-FU toxicity.
Deficiency in human DPD is associated with autosomal recessive disease, thymine-uraciluria, and with severe 5-fluorouracil toxicity in cancer patients.