Genotyping of a family with a novel deleterious <i>DPYD</i> mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio

Thomas, Fabienne; Hennebelle, Isabelle; Delmas, Caroline; Lochon, Isabelle; Dhelens, C.; Tixidre, Claire Garnier; Bonadona, Agnès; Penel, Nicolas; Gonçalvès, Anthony; Delord, J.P.; Toulas, Christine; Chatelut, Étienne

doi:10.1002/cpt.210

Cited by 36 publications

(25 citation statements)

References 41 publications

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“…This poor correlation between physiological pyrimidine concentrations and DPD enzyme activity may reflect the fact that, under low physiological U concentrations, DPD enzyme is not saturated, suggesting that only a marked DPD deficiency can impact physiological U and UH2 concentrations. Accordingly, literature data show that, in most cases, lethal toxicity is associated with a markedly deficient phenotype based on physiological pyrimidines in plasma [10,12,31], or enzyme activity [5]. In line, the lethal toxicity observed in the present study occurred in a patient presenting elevated U plasma concentration (above the 91 st percentile).…”

Section: Discussionsupporting

confidence: 82%

“…Four patients carried the E412E allele (heterozygous) and were also the only ones to exhibit c.483+18G>A variation (heterozygous), strongly suggesting that they carried HapB3. As concerns INDELs, the relevant duplication c.168_175dupGAATAATT in exon 3 ( in silico pathogenic) identified in a DPD-deficient patient with lethal toxicity [31] was not found in the present patient cohort.…”

Section: Discussionmentioning

confidence: 83%

“…In order to mimic routine DPD-deficiency screening and ensure robustness, frozen plasmas were sent to one of 3 measuring laboratories (according to geographic location). Depending on the laboratory, solid-phase or liquid-liquid extraction followed by HPLC analysis (UV detection) of uracil (U) and dihydrouracil (UH2) was performed [29–31]. Limit of quantification was 7 to 25 ng/ml for UH2 and 3 to 6 ng/ml for U, depending on the laboratory.…”

Section: Methodsmentioning

confidence: 99%

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New advances in DPYD genotype and risk of severe toxicity under capecitabine

et al. 2017

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BackgroundDeficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine.MethodsTwo-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3’UTR and 5’UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement.ResultsAmong the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3–4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p<0.001) but not with grade 4 toxicity. Considering additional deleterious coding variants D342G, S492L, R592W and F100L increased the sensitivity to 26.7% for grade 3–4 toxicity (PPV 72.7%, RR 7.6, p<0.001), and was significantly associated with grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001), suggesting the clinical relevance of extended targeted DPYD genotyping. As compared to extended genotype, combining genotyping (7 variants) and phenotyping (U>16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR.ConclusionsExploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3–4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

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New advances in DPYD genotype and risk of severe toxicity under capecitabine

et al. 2017

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“…A partial or complete DPD deficiency leads to severe adverse effects in patients who receive 5-FU-based treatments (van Kuilenburg, 2004;Al-Sanna'a et al, 2005). Currently, more than 450 DPYD polymorphisms have been identified as the cause of 5-FU-related toxicity in cancer-related treatments (Sistonen et al, 2012;Thomas et al, 2016;Vaudo et al, 2016;van Kuilenburg et al, 2017). Some of these variants are known to alter mRNA splicing or the protein sequence, resulting in reduced enzymatic activity.…”

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confidence: 99%

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

et al. 2018

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“…It may therefore be difficult to introduce DPYD genotyping as useful prospective screening in Japan. Previously, analysis of DPD enzyme activity has been proposed to be the most reliable method for identifying at‐risk patients 23 . For the interpretation of a novel or very rare DPYD variant, it is useful to measure the DPD activity in the individuals who carry the variants.…”

Section: Discussionmentioning

confidence: 99%

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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Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio

Cited by 36 publications

References 41 publications

New advances in DPYD genotype and risk of severe toxicity under capecitabine

New advances in DPYD genotype and risk of severe toxicity under capecitabine

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

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

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