Contribution of dihydropyrimidinase gene alterations to the development of serious toxicity in fluoropyrimidine-treated cancer patients

Fidlerová, J; Kleiblová, Petra; Bilek, Matej; Kormunda, Stanislav; Formankova, Zuzana; Novotný, Jan; Kleibl, Zdeněk

doi:10.1007/s00280-009-1071-0

Cited by 26 publications

(13 citation statements)

References 27 publications

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“…There are some reports of variants in DPYS that may explain the occurrence of severe toxicity from FP‐based chemotherapy. For example, c.−1T>C is a common noncoding variant in this gene reported to have an impact on toxicity in patients receiving FP 24 . Our current results have also revealed a high allele frequency of 68% for c.−1T>C, but did not demonstrate a clear relationship between FP‐related high toxicity and this variant.…”

Section: Discussioncontrasting

confidence: 72%

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: Discussioncontrasting

confidence: 72%

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 rare coding region variant rs36027551 ( DPYS c.541C>T, p.Arg181Trp) was polymorphic but was not significantly associated with toxicity (5 carriers observed; 1 carrier experienced toxicity; P =1.00). The common intron 1 sequence variant rs2669429 (c.265-58T>C) previously reported to protect against side effects (Fidlerova et al , 2010) was not significantly associated with protection from diarrhoea, mucositis and/or neutropaenia (Table 7; P =0.513).…”

Section: Resultsmentioning

confidence: 91%

“…However, in our study, only one out of the three DPYS coding SNPs genotyped was polymorphic in the cohort and no significant associations were found. The intron 1 sequence variant rs2669429 (c.265-58T>C), previously reported to protect against side effects (Fidlerova et al , 2010), was not significantly associated with protection from diarrhoea, mucositis and/or neutropaenia.…”

Section: Discussionmentioning

confidence: 89%

Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity

et al. 2013

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Background:Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.Methods:Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models.Results:Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3–4 toxicity (P<0.0001). The TYMS 3′-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38–6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand–foot syndrome (P=4.1 × 10−6, OR=9.99, 95% CI: 3.84–27.8). The linked CDA c.−92A>G and CDA c.−451C>T variants predicted grade 2–4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3–4.2 and P=0.0082, OR=2.3, 95% CI: 1.3–4.2, respectively).Conclusion:We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.

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“…DHP is involved in the reductive degradation of pyrimidines and catalyzes the second step in the formation of β-alanine from uracil. SNP rs2669429 has been previously reported to correlate with DHP-mediated fluoropyrimidine metabolism (Fidlerova et al 2010). Furthermore, rs2669429 was found to be located in a binding site of the hepatic transcription factor HNF1 (Thomas et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Novel plasma biomarker of atenolol-induced hyperglycemia identified through a metabolomics-genomics integrative approach

et al. 2016

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Introduction While atenolol is an effective antihypertensive agent, its use is also associated with adverse events including hyperglycemia and incident diabetes that may offset the benefits of blood pressure lowering. By combining metabolomic and genomic data acquired from hypertensive individuals treated with atenolol, it may be possible to better understand the pathways that most impact the development of an adverse glycemic state. Objective To identify biomarkers that can help predict susceptibility to blood glucose excursions during exposure to atenolol. Methods Plasma samples acquired from 234 Caucasian participants treated with atenolol in the Pharmacogenomic Evaluation of Antihypertensive Responses trial were analyzed by gas chromatography Time-Of-Flight Mass Spectroscopy. Metabolomics and genomics data were integrated by first correlating participant’s metabolomic profiles to change in glucose after treatment with atenolol, and then incorporating genotype information from genes involved in metabolite pathways associated with glucose response. Results Our findings indicate that the baseline level of β-alanine was associated with glucose change after treatment with atenolol (Q = 0.007, β = 2.97 mg/dL). Analysis of genomic data revealed that carriers of the G allele for SNP rs2669429 in gene DPYS, which codes for dihydropyrimidinase, an enzyme involved in β-alanine formation, had significantly higher glucose levels after treatment with atenolol when compared with non-carriers (Q = 0.05, β = 2.76 mg/dL). This finding was replicated in participants who received atenolol as an add-on therapy (P = 0.04, β = 1.86 mg/dL). Conclusion These results suggest that β-alanine and rs2669429 may be predictors of atenolol-induced hyperglycemia in Caucasian individuals and further investigation is warranted.

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Contribution of dihydropyrimidinase gene alterations to the development of serious toxicity in fluoropyrimidine-treated cancer patients

Abstract: Our results indicate that missense and nonsense variants in DPYS are infrequent, however, the development of serious primarily gastrointestinal toxicity could be influenced by non-coding DPYS sequence variants c.-1T>C and IVS1-58T>C.

Cited by 26 publications

References 27 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

Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity

Novel plasma biomarker of atenolol-induced hyperglycemia identified through a metabolomics-genomics integrative approach

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