Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity

Nakajima, Yoko; Meijer, Judith; Dobritzsch, Doreen; Ito, Tetsuya; Zhang, Chunhua; Wang, Xu; Watanabe, Yoriko; Tashiro, Kunio; Meinsma, Rutger; Roelofsen, Jeroen; Zoetekouw, Lida; Kuilenburg, André B. P.

doi:10.1016/j.ymgme.2017.10.003

Cited by 19 publications

(11 citation statements)

References 40 publications

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“…It is known that the Japanese prevalence of βUP deficiency is relatively high (1 per 6000 newborns) 19 . We have also reported that some DPYS variants may be more common than expected in East Asian groups 20 . These findings have prompted us to screen for variants of the genes associated with FP‐related toxicity in Japanese subjects.…”

Section: Introductionmentioning

confidence: 85%

Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer

et al. 2020

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Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype‐guided dose individualization of FP therapy has been proposed in western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP‐related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intron regions of their DPYD, DPYS, and UPB1 genes. In total, 24 single nucleotide variants (15 in DPYD, 7 in DPYS and 2 in UPB1) were identified including 3 novel variants in DPYD and 1 novel variant in DPYS. We did not find a significant association between FP‐related high toxicity and each of these individual variants, although a certain trend toward significance was observed for p.Arg181Trp and p.Gln334Arg in DPYS (P = .0813 and .087). When we focused on 7 DPYD rare variants (p.Ser199Asn, p.IIe245Phe, p.Thr305Lys, p.Glu386Ter, p.Ser556Arg, p.Ala571Asp, p.Trp621Cys) which have an allele frequency of less than 0.01% in the Japanese population and are predicted to be loss‐of‐function mutations by in silico analysis, the group of patients who were heterozygous carriers of at least one these rare variants showed a strong association with FP‐related high toxicity (P = .003). Although the availability of screening of these rare loss‐of‐function variants is still unknown, our data provide useful information that may help to alleviate FP‐related toxicity in Japanese patients with cancer.

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Section: Introductionmentioning

confidence: 85%

Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer

et al. 2020

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“…The clinical phenotype of DHP-deficient patients is highly variable, ranging from asymptomatic to exhibiting symptomatology similar to that of DPD deficiency, including seizures, intellectual disability, growth impairment, and dysmorphic facial features [70][71][72]. To date, 35 genetically confirmed patients with DHP deficiency have been reported [33,[73][74][75][76][77]. However, potential asymptomatic deficiencies might be present in a population with a low frequency of DPD deficiencies.…”

Section: Dihydropyrimidinase (Dhp)mentioning

confidence: 99%

“…Nakajima et al reported two Chinese pediatric patients with DHP deficiency caused by the compound DPYS heterozygous mutation c.1001A > G and c.1443 + 5G > A (exon 8 skipping) [81]. Moreover, Nakajima et al identified eight variants, including four novel missense mutations and one novel deletion in four DHP-deficient patients [77]. Thus, DPYS polymorphisms could emerge as novel pharmacogenomic markers associated with severe FP-related toxicity in diverse global populations.…”

Section: Dihydropyrimidinase (Dhp)mentioning

confidence: 99%

In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

Hishinuma

Rico

Hiratsuka

2020

JCM

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Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in Escherichia coli or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms.

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“…Previously, we reported a Japanese patient with severe capecitabine-related toxicity associated with DHPase deficiency due to a compound heterozygous mutation in the DPYS gene causing two enzyme loss of function mutations, c.1001A>G (p.Q334R) and c.1393C>T (p.R465X) (Hiratsuka et al, 2015). Nakajima et al identified (Nakajima et al, 2017). Notably, the identification of these DHPase-deficient patients can be attributed to recently enhanced diagnostic efforts in Asian populations Nakajima et al, 2016).…”

Section: Introductionmentioning

confidence: 98%

Functional Characterization of 12 Dihydropyrimidinase Allelic Variants in Japanese Individuals for the Prediction of 5-Fluorouracil Treatment-Related Toxicity

et al. 2022

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The drug 5-fluorouracil (5-FU) is the first-choice chemotherapeutic agent against advanced-stage cancers. However, 10-30% of treated patients experience grade 3-4 toxicity. The deficiency of dihydropyrimidinase (DHPase), which catalyzes the second step of the 5-FU degradation pathway, is correlated with the risk of developing toxicity. Thus, genetic polymorphisms within DPYS, the DHPase-encoding gene, could potentially serve as predictors of severe 5-FU-related toxicity. We identified 12 novel DPYS variants in 3,554 Japanese individuals, but the effects of these mutations on function remain unknown. In the current study, we performed in vitro enzymatic analyses of the 12 newly identified DHPase variants. Dihydrouracil or dihydro-5-FU hydrolytic ring-opening kinetic parameters, K m and V max , and intrinsic clearance (CL int = V max /K m ) of the wild-type DHPase and eight variants were measured. Five of these variants (R118Q, H295R, T418I, Y448H, and T513A) showed significantly reduced CL int compared with that in the wild-type. The parameters for the remaining four variants (V59F, D81H, T136M, and R490H) could not be determined as dihydrouracil and dihydro-5-FU hydrolytic ring-opening activity was undetectable. We also determined DHPase variant protein stability using cycloheximide and bortezomib. The mechanism underlying the observed changes in the kinetic parameters was clarified

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Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity

Cited by 19 publications

References 40 publications

Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer

Impact of DPYD, DPYS, and UPB1 gene variations on severe drug‐related toxicity in patients with cancer

In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

Functional Characterization of 12 Dihydropyrimidinase Allelic Variants in Japanese Individuals for the Prediction of 5-Fluorouracil Treatment-Related Toxicity

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