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

Yokoi, Katsuyuki; Nakajima, Yoko; Matsuoka, Hiroshi; Shinkai, Yasuko; Ishihara, Takuma; Maeda, Yasuhiro; Kato, Takema; Katsuno, Hidetoshi; Masumori, Koji; Kawada, Kenji; Yoshikawa, Tetsushi; Ito, Tetsuya; Kurahashi, Hiroki

doi:10.1111/cas.14553

Cited by 15 publications

(17 citation statements)

References 27 publications

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“…Further example of ethnic heterogeneity within the Japanese population has been demonstrated by Yokoi et al, who investigated DPYD variants in 301 patients undergoing FP-based chemotherapy (among other exploratory gene variants). 33 They found 15 DPYD variants, 7 of which were further evaluated in silico and were found to have probable pathogenic effects. Clinically, heterozygous carriers of each of these 7 variants developed grade 3 toxicities, including neutropaenia and/or diarrhoea and vomiting.…”

Section: Frequency Of Typical and Novel Dpyd Variants In Non-caucasian Populationsmentioning

confidence: 99%

“…Grade 3 toxicity incidence in the remaining wild-type cohort was 17%, 50/294. 33 Yokoi identified that each pathogenic variant carrier was different and that this would pose an issue for pre-treatment screening panels in Japanese populations. Caucasian variants and others described within this review were also not detected in this Japanese cohort.…”

Section: Frequency Of Typical and Novel Dpyd Variants In Non-caucasian Populationsmentioning

confidence: 99%

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Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

White¹,

Scott²,

Paul³

et al. 2021

PGPM

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Pharmacogenomic screening can identify patients with gene variants that predispose them to the development of severe toxicity from fluoropyrimidine (FP) chemotherapy. Deficiency of the critical metabolic enzyme dihydropyrimidine dehydrogenase (DPD) leads to excessive toxicity on exposure to fluoropyrimidine chemotherapy. This can result in hospitalisation, intensive care admissions and even death. Upfront screening of the gene that encodes for DPD ( DPYD ) has recently been implemented in regions throughout Europe and the United Kingdom. Current screening evaluates DPYD variants that are well described within Caucasian patient populations and provides genotyped-guided dose adjustment recommendations based upon the presence of these variants. This article reviews the differences in DPYD gene variants within non-Caucasian populations compared to Caucasian populations, with regard to the implications for clinical tolerance of fluoropyrimidine chemotherapies and genotype guided dose adjustment guidelines.

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Section: Frequency Of Typical and Novel Dpyd Variants In Non-caucasian Populationsmentioning

confidence: 99%

Section: Frequency Of Typical and Novel Dpyd Variants In Non-caucasian Populationsmentioning

confidence: 99%

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

White¹,

Scott²,

Paul³

et al. 2021

PGPM

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“…Besides, for cancer patients, UPB1 was screened as a prognostic circulating biomarker or signature for patients with hepatocellular carcinoma ( 34 , 35 ), similar to clear renal cell carcinoma ( 36 ). In addition, for the treatment of specific tumors, especially the 5-fluorouracil treatment of colorectal cancer, some researchers explored the role of UPB1 in the 5-fluorouracil pathway or fluoropyrimidine-related high toxicity ( 37 , 38 ). What’s more, we not only introduced UPB1 in the clinical prognostic analysis of LUAD for the first time but also found the expression of UPB1 was correlated with CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

A robust CD8+ T cell-related classifier for predicting the prognosis and efficacy of immunotherapy in stage III lung adenocarcinoma

Feng

Xu²,

Zhang³

et al. 2022

Front. Immunol.

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Patients with stage III lung adenocarcinoma (LUAD) have significant survival heterogeneity, meanwhile, CD8+ T cell has a remarkable function in immunotherapy. Therefore, developing novel biomarkers based on CD8+ T cell can help evaluate the prognosis and guide the strategy of immunotherapy for patients with stage III LUAD. Thus, we abstracted twelve datasets from multiple online databases and grouped the stage III LUAD patients into training and validation sets. We then used WGCNA and CIBERSORT, while univariate Cox analysis, LASSO analysis, and multivariate Cox analysis were performed. Subsequently, a novel CD8+ T cell-related classifier including HDFRP3, ARIH1, SMAD2, and UPB1 was developed, which could divide stage III LUAD patients into high- and low-risk groups with distinct survival probability in multiple cohorts (all P < 0.05). Moreover, a robust nomogram including the traditional clinical parameters and risk signature was constructed, and t-ROC, C-index, and calibration curves confirmed its powerful predictive capacity. Besides, we detected the difference in immune cell subpopulations and evaluated the potential benefits of immunotherapy between the two risk subsets. Finally, we verified the correlation between the gene expression and CD8+ T cells included in the model by immunohistochemistry and validated the validity of the model in a real-world cohort. Overall, we constructed a robust CD8+ T cell-related risk model originally which could predict the survival rates in stage III LUAD. What’s more, this model suggested that patients in the high-risk group could benefit from immunotherapy, which has significant implications for accurately predicting the effect of immunotherapy and evaluating the prognosis for patients with stage III LUAD.

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“…The Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG) have established guidelines on 5-FU dosage adjustment based on DPYD genetic polymorphisms ( Henricks et al, 2015 ; Amstutz et al, 2018 ; Lunenburg et al, 2020 ). However, there are considerable geographical-ethnicity differences in the variation and frequency of DPYD genetic polymorphisms, and these four DPYD risk variants have not been identified in Asian populations, including the Japanese population ( van Kuilenburg, 2004 ; Maekawa et al, 2007 ; Yokoi et al, 2020 ). We previously reported enzymatic functional alterations in 21 DPD variants identified by whole-genome sequencing (WGS) of 1,070 Japanese individuals, suggesting that some DPD variants specific to the Japanese population may be responsible for the development of severe 5-FU toxicity ( Hishinuma et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population

et al. 2022

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Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. In Caucasians, four DPYD risk variants are recognized to be responsible for interindividual variations in the development of 5-FU toxicity. However, these risk variants have not been identified in Asian populations. Recently, 41 DPYD allelic variants, including 15 novel single nucleotide variants, were identified in 3,554 Japanese individuals by analyzing their whole-genome sequences; however, the effects of these variants on DPD enzymatic activity remain unknown. In the present study, an in vitro analysis was performed on 41 DPD allelic variants and three DPD risk variants to elucidate the changes in enzymatic activity. Wild-type and 44 DPD-variant proteins were heterologously expressed in 293FT cells. DPD expression levels and dimerization of DPD were determined by immunoblotting after SDS-PAGE and blue native PAGE, respectively. The enzymatic activity of DPD was evaluated by quantification of dihydro-5-FU, a metabolite of 5-FU, using high-performance liquid chromatography-tandem mass spectrometry. Moreover, we used 3D simulation modeling to analyze the effect of amino acid substitutions on the conformation of DPD. Among the 41 DPD variants, seven exhibited drastically decreased intrinsic clearance (CLint) compared to the wild-type protein. Moreover, R353C and G926V exhibited no enzymatic activity, and the band patterns observed in the immunoblots after blue native PAGE indicated that DPD dimerization is required for its enzymatic activity. Our data suggest that these variants may contribute to the significant inter-individual variability observed in the pharmacokinetics and pharmacodynamics of 5-FU. In our study, nine DPD variants exhibited drastically decreased or no enzymatic activity due to dimerization inhibition or conformational changes in each domain. Especially, the rare DPYD variants, although at very low frequencies, may serve as important pharmacogenomic markers associated with the severe 5-FU toxicity in Japanese population.

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

Cited by 15 publications

References 27 publications

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

A robust CD8+ T cell-related classifier for predicting the prognosis and efficacy of immunotherapy in stage III lung adenocarcinoma

Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population

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