Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene

Maring, Jan Gerard; Kuilenburg, André B. P.; Haasjes, Janet; Piersma, Harry L.; Groen, Henk; Uges, Donald; Gennip, Albert H.; Vries, Elisabeth G.E. de

doi:10.1038/sj.bjc.6600208

Cited by 81 publications

(42 citation statements)

References 15 publications

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“…DPYD plays an essential role in inactivating 5-FU by catalyzing conversion of 5-FU to fluoro-5,6-dihydrouracil (FUH 2 ) (44). Indeed DPYD deficiency, for example, by inactivating mutation or by polymorphism, directly contributes to 5-FU toxicity in patients (45,46). On the other hand, increased DPYD activity in HCC patient samples has been attributed to the inherent resistance of HCC to 5-FU and the relatively low level of DPYD in colorectal cancer explains the reason why colorectal cancer is sensitive to 5-FU (47,48).…”

Section: Discussionmentioning

confidence: 99%

Identification of genes conferring resistance to 5-fluorouracil

Yoo

Gredler

Vozhilla

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

135

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Section: Discussionmentioning

confidence: 99%

Identification of genes conferring resistance to 5-fluorouracil

Yoo

Gredler

Vozhilla

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

135

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“…[48][49][50] In patients who are deficient for DPD, 5-FU clearance is dramatically reduced and standard doses of 5-FU cause excessive toxicity in these patients. 48,51,52 The frequency of DPD deficiency has been estimated to be as high as 2-3% in Caucasians based on measurements of DPD activity in peripheral mononuclear cells in patients and healthy volunteers 53,54 This percentage is probably high enough to justify screening on DPD deficiency prior to 5-FU-based chemotherapy. Instead of screening for specific mutations in the DPYD gene, Mattison et al 55 developed a simple uracil breath test for DPD phenotyping, based on the release of 13 CO 2 from 2-13 C uracil in the presence of intact DPD.…”

Section: -Fluorouracilmentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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“…Sequencing revealed a homozygous splice mutation in DPYD previously associated with recessive DPD deficiency and 5-fluorouracil toxicity. 32,35 The diagnosis of DPD deficiency was confirmed by subsequent urine tests that showed highly elevated uracil (395 mmol/moL creatinine; reference range ,28) and thymine (300 mmoL/moL creatinine; reference range ,6).…”

Section: Figurementioning

confidence: 99%

Targeted exome sequencing of suspected mitochondrial disorders

et al. 2013

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Objective: To evaluate the utility of targeted exome sequencing for the molecular diagnosis of mitochondrial disorders, which exhibit marked phenotypic and genetic heterogeneity. Methods:We considered a diverse set of 102 patients with suspected mitochondrial disorders based on clinical, biochemical, and/or molecular findings, and whose disease ranged from mild to severe, with varying age at onset. We sequenced the mitochondrial genome (mtDNA) and the exons of 1,598 nuclear-encoded genes implicated in mitochondrial biology, mitochondrial disease, or monogenic disorders with phenotypic overlap. We prioritized variants likely to underlie disease and established molecular diagnoses in accordance with current clinical genetic guidelines.Results: Targeted exome sequencing yielded molecular diagnoses in established disease loci in 22% of cases, including 17 of 18 (94%) with prior molecular diagnoses and 5 of 84 (6%) without. The 5 new diagnoses implicated 2 genes associated with canonical mitochondrial disorders (NDUFV1, POLG2), and 3 genes known to underlie other neurologic disorders (DPYD, KARS, WFS1), underscoring the phenotypic and biochemical overlap with other inborn errors. We prioritized variants in an additional 26 patients, including recessive, X-linked, and mtDNA variants that were enriched 2-fold over background and await further support of pathogenicity. In one case, we modeled patient mutations in yeast to provide evidence that recessive mutations in ATP5A1 can underlie combined respiratory chain deficiency. Conclusion:The results demonstrate that targeted exome sequencing is an effective alternative to the sequential testing of mtDNA and individual nuclear genes as part of the investigation of mitochondrial disease. Our study underscores the ongoing challenge of variant interpretation in the clinical setting. Mitochondrial disorders are a heterogeneous collection of rare disorders caused by mitochondrial dysfunction.1 Multiple organ systems can be affected, with features that can include myopathy, encephalopathy, seizures, lactic acidosis, sensorineural deafness, optic atrophy, diabetes mellitus, liver failure, and ataxia.2 Mitochondrial disorders can be caused by mutations in the nuclear or mitochondrial genomes, and more than 100 genetic loci have been identified to date.3,4 Whereas these disorders may be inherited in a maternal, recessive, X-linked, or dominant manner, many patients have no obvious family history of the disorder.5-7 Because of phenotypic and locus heterogeneity, traditional sequential genetic tests result in molecular diagnoses for only a fraction of patients.8 Limitations in traditional genetic testing have motivated our group and others to develop "next-generation sequencing" (NGS) approaches for molecular diagnosis.

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Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene

Cited by 81 publications

References 15 publications

Identification of genes conferring resistance to 5-fluorouracil

Identification of genes conferring resistance to 5-fluorouracil

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Targeted exome sequencing of suspected mitochondrial disorders

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