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

Hishinuma, Eiji; Narita, Yoko; Rico, Evelyn Marie Gutiérrez; Ueda, Akiko; Obuchi, Kai; Tanaka, Yoshikazu; Saitō, Sakae; Tadaka, Shu; Kinoshita, Kengo; Maekawa, Masamitsu; Mano, Nariyasu; Nakayoshi, Tomoki; Oda, Akifumi; Hirasawa, Noriyasu; Hiratsuka, Masahiro

doi:10.1124/dmd.122.001045

Cited by 3 publications

(1 citation statement)

References 34 publications

(51 reference statements)

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“…[18] found 8 novel and rare DPYS variants (c.210delG, c.7580G>A, c.884A>G, c.1001A>G, c.1253C>T, c.1393C>T, c.1468C>T and c.1469G>A) in DHP-deficient patients, determined from abnormal 5,6-dihydrouracil levels, and also demonstrated decreased DHP activity in vitro . Additional studies have characterized the in vitro activity of rare and novel missense DPYS variants previously found in Japanese cohorts [10,19]. Moreover, a recent paper used a Sequence Kernel Association Test analysis to demonstrate that the burden of carrying at least one rare DPYS variation was associated with an increased risk of toxicity by over 4-fold [20].…”

Section: Discussionmentioning

confidence: 99%

Common dihydropyrimidinase (DPYS) genetic variations do not predict fluoropyrimidine-related chemotherapy toxicity in a Canadian cohort

Medwid,

Mailloux,

Wigle

et al. 2024

Pharmacogenetics and Genomics

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Known genetic variations in dihydropyrimidine dehydrogenase (gene name DPYD) do not fully predict patients at risk for severe fluoropyrimidine-associated chemotherapy toxicity. Dihydropyrimidinase (gene name DPYS), the second catabolic enzyme in fluoropyrimidine metabolism, has been noted as a potential determinant of variation in fluoropyrimidine metabolism and response. In this study, we genotyped for DPYS c.-1T>C (rs2959023), c.265-58T>C (rs2669429) and c.541C>T (rs36027551) in a Canadian cohort of 248 patients who were wild type for Clinical Pharmacogenetics Implementation Consortium recommended DPYD variants and had received a standard dose of fluoropyrimidine chemotherapy. None of our patients were found to carry the DPYS c.541C>T variant, while the minor allele frequencies were 63% and 54% for c.-1T>C and c.265-58T>C, respectively. There was no association between DPYS c.-1T>C wild type and heterozygote [odds ratio (OR) (95% confidence interval, CI) = 1.10 (0.51–2.40)] or homozygote variant carriers [OR (95% CI) = 1.22 (0.55–2.70)], or between DPYS c.265-58T>C wild-type patients and heterozygote [OR (95% CI) = 0.93 (0.48–1.80)] or homozygote variant carriers [OR (95% CI) = 0.76 (0.37–1.55)] in terms of fluoropyrimidine-associated toxicity. Therefore, in our cohort of mostly Caucasian Canadians, genetic variations in DPYS do not appear to be a significant contributor to severe fluoropyrimidine-associated toxicity.

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Section: Discussionmentioning

confidence: 99%

Common dihydropyrimidinase (DPYS) genetic variations do not predict fluoropyrimidine-related chemotherapy toxicity in a Canadian cohort

Medwid,

Mailloux,

Wigle

et al. 2024

Pharmacogenetics and Genomics

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jMorp: Japanese Multi-Omics Reference Panel update report 2023

Tadaka,

Kawashima,

Hishinuma

et al. 2023

Nucleic Acids Research

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Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.

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The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity

De Mattia,

Polesel,

Silvestri

et al. 2023

Hum Genomics

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Background Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity. Methods The coding sequence and untranslated regions of 54 genes related to fluoropyrimidine pharmacokinetics/pharmacodynamics were analyzed by next-generation sequencing in 120 patients developing grade 3–5 toxicity (NCI-CTC vs3.0) and 104 matched controls. Sequence Kernel Association Test (SKAT) analysis was used to select genes with a burden of genetic variants significantly associated with risk of severe toxicity. The statistical association of common and rare genetic variants in selected genes was further investigated. The functional impact of genetic variants was assessed using two different in silico prediction tools (Predict2SNP; ADME Prediction Framework). Results SKAT analysis highlighted DPYS and PPARD as genes with a genetic mutational burden significantly associated with risk of severe fluoropyrimidine-related toxicity (Bonferroni adjusted P = 0.024 and P = 0.039, respectively). Looking more closely at allele frequency, the burden of rare DPYS variants was significantly higher in patients with toxicity compared with controls (P = 0.047, Mann–Whitney test). Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity. The burden of PPARD rare genetic variants was not significantly related to toxicity. Some common variants with predictive value in DPYS and PPARD were also identified: DPYS rs143004875-T and PPARD rs2016520-T variants predicted an increased risk of severe cumulative (P = 0.002 and P = 0.001, respectively) and acute (P = 0.005 and P = 0.0001, respectively) toxicity. Conclusion This work demonstrated that the rare mutational burden of DPYS, a gene strictly cooperating with DPYD in the catabolic pathway of fluoropyrimidines, is a promising pharmacogenetic marker for precision dosing of fluoropyrimidines. Additionally, some common genetic polymorphisms in DPYS and PPARD were identified as promising predictive markers that warrant further investigation.

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

Cited by 3 publications

References 34 publications

Common dihydropyrimidinase (DPYS) genetic variations do not predict fluoropyrimidine-related chemotherapy toxicity in a Canadian cohort

Common dihydropyrimidinase (DPYS) genetic variations do not predict fluoropyrimidine-related chemotherapy toxicity in a Canadian cohort

jMorp: Japanese Multi-Omics Reference Panel update report 2023

The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity

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