Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals

Hishinuma, Eiji; Narita, Yoko; Saitō, Sakae; Maekawa, Masamitsu; Akai, Fumika; Nakanishi, Yuya; Yasuda, Jun; Nagasaki, Masao; Yamamoto, Masayuki; Yamaguchi, Hiroaki; Mano, Nariyasu; Hirasawa, Noriyasu; Hiratsuka, Masahiro

doi:10.1124/dmd.118.081737

Cited by 36 publications

(47 citation statements)

References 28 publications

(32 reference statements)

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“…A recent study has reported the functional characterization of 21 allelic variants of DPYD identified in 1070 Japanese individuals 14 . Five of the variants (p.Val335Met, p.IIe543Val, p.Val732IIe, p.Thr768Lys, p.Asn893Ser) identified in our present analysis were among those described in that earlier study.…”

Section: Discussionsupporting

confidence: 70%

“…More than 450 DPYD variants have been identified to date as a cause of 5FU‐related toxicity in patients with cancer 14 . In the context of 5FU, 4 DPYD variants identified in the White population are known to have an impact on enzyme function and FP‐related toxicity risk 21 .…”

Section: Discussionmentioning

confidence: 99%

“…Hence, DPYD genotype‐guided dose individualization of FP therapy has now been conducted in some western countries 10 . However, to our knowledge it has not been performed yet in Japan, possibly because none of these DPYD variants have been identified in the Asian population 14 . Recently, 21 DPYD allelic variants were identified in 1070 healthy Japanese individuals 15 .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, 21 DPYD allelic variants were identified in 1070 healthy Japanese individuals 15 . The functional alterations caused by these variants were analyzed in vitro and their enzyme activities were characterized 14 . However, there has been no report to date on the clinical relevance of DPYD variants as predictors of FP‐associated toxicity in Japanese people.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…For example, the IRUD project (Japan's Initiative on Rare and Undiagnosed Diseases 9 ) used the reference panel to reduce the discovery of false positive single nucleotide variants (SNVs) during the exome analyses of undiagnosed patients. In another project, CYP SNVs included in the reference panels were selected and analyzed systematically for their effect on drug metabolism [10][11][12] . As seen from these examples, the previous versions of the reference panels worked well; however, there are some limitations.…”

Section: Background and Summarymentioning

confidence: 99%

3.5KJPNv2, An allele frequency panel of 3,552 Japanese Individuals

Tadaka

Katsuoka

Ueki

et al. 2019

Preprint

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The first step towards realizing personalized healthcare is to catalog the genetic variations in a population. Since the dissemination of individual-level genomic information is strictly controlled, it will be useful to construct population-level allele frequency panels and to provide them through easy-to-use interfaces.In the Tohoku Medical Megabank Project, we have sequenced nearly 4,000 individuals from a Japanese population, and constructed an allele frequency panel of 3,552 individuals after removing related samples. The panel is called the 3.5KJPNv2. It was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. Our database is the first largescale panel providing the frequencies of variants present on the X chromosome and on the mitochondria in the Japanese population. All the data are available on our original database at https://jmorp.megabank.tohoku.ac.jp. new panel construction by using a pipeline similar to the 1KGP and gnomAD pipelines. We also report the variant frequencies of X chromosome and those of mitochondria, which makes this the first such report to do so on a largescale for the Japanese population. Methods Sample InformationParticipants' declared age, and their sex as determined from X-and Y-chromosome sequencing are presented in Table 1 (b). Samples with irregular karyotypes, such as those with Turner syndrome, were excluded. Close relatives of individual subjects, based on mean identityby-descent (IBD; PIHAT in PLINK version 1.07) values indicating relatedness closer than between third cousins degree relatives, were excluded. Whole-genome sequencingLibrary preparation and sequencing were performed as described earlier with minor modifications 5 . Briefly, genomic DNA extracted from the buffy coat was fragmented by sonication to an average target size of 550 bp. After library quantification using the quantitative MiSeq method 15 , sequencing was performed on the HiSeq 2500 system (Illumina). The TruSeq Rapid PE Cluster V1 and SBS Kits (1 sample per flowcell), and the TruSeq Rapid PE Cluster Kit V2 and SBS Kit (2 samples per flowcell) were used for 162-bp and 259-bp paired-end protocols, respectively.

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Poor association between dihydropyrimidine dehydrogenase (DPYD) genotype and fluoropyrimidine‐induced toxicity in an Asian population

Kanai

Kawaguchi

Kotaka³

et al. 2022

Cancer Medicine

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Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals

Cited by 36 publications

References 28 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

3.5KJPNv2, An allele frequency panel of 3,552 Japanese Individuals

Poor association between dihydropyrimidine dehydrogenase (DPYD) genotype and fluoropyrimidine‐induced toxicity in an Asian population

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