Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5-fluorouracil-related side effects

Abstract

M166V, S534N, I543V) displayed significantly reduced DPD activity. The rare combination of the highly conserved mutation sites M166V and S534N was additionally found in one of the other patients. DPD enzyme activity was low, but yet within normal range. The K259E mutation did not provoke a decrease in DPD function in a heterozygous individual. Based on the protein structure of crystalline pig DPD and the deduced homology models, we have additionally investigated the amino acid positions in their three-dimensional network which correspond to the five missense mutations discovered in the patients.

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

“…The novel DPYD variants c.187A>G (K63E) and c.1050 G>A (R357H) were found only in one woman (with neutropenia grade 4 and diarrhea grade 3) and one man (with diarrhea grade 4), respectively. Rare alteration c.775A>G (K259E), reported previously twice in high-and low-toxicity German patients, respectively, was found in combination with C29R and V732I in one man (with leucopenia grade 3 and neutropenia grade 4) [14,27].…”

“…The homology modeling (Fig. 1A) based on crystallography data of porcine DPD enzyme (93% identity to human homologue) indicates the proximity of lysine 63 to FAD binding site in domain II [8,14]. The change of lysine 63 to negatively charged glutamate might therefore influence the electron transfer pathway.…”

“…IVS14+1G>A), the biological effect of many, mainly missense variants (e.g. M166V or C29R) remained controversial [13][14][15][16][17].…”

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

“…a All SNPs are in the same block J Hum Genet (2007) 52: 804-819 815 detected in the patient exhibiting severe mucositis during cyclophosphamide/methotrexate/5-FU chemotherapy (Gross et al 2003). Furthermore, the adjacent Leu261 interacts via the main chain atoms with the N6, N1, and N3 atoms of adenine of FAD, and has an important role in the proper orientation of the adenine moiety in the FADbinding pocket (Dobritzsch et al 2001).…”

“…To date, at least 30 variant DPYD alleles have been published, with or without deleterious impact upon DPD activity (Gross et al 2003;Ogura et al 2005;Seck et al 2005;van Kuilenburg 2004;Zhu et al 2004). Of these variations, a splice site polymorphism, IVS14 + 1G[A, which causes skipping of exon 14, is occasionally detected in North Europeans with allele frequencies of 0.01-0.02 (van Kuilenburg 2004).…”