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Robert B. Diasio - One of the best experts on this subject based on the ideXlab platform.
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gene specific variant classifier dpyd varifier to identify deleterious alleles of Dihydropyrimidine Dehydrogenase
Clinical Pharmacology & Therapeutics, 2018Co-Authors: Shikshya Shrestha, Steven M Offer, Cheng Zhang, Calvin R Jerde, Qian Nie, Robert B. DiasioAbstract:Deleterious variants in Dihydropyrimidine Dehydrogenase (DPD, DPYD gene) can be highly predictive of clinical toxicity to the widely prescribed chemotherapeutic 5-fluorouracil (5-FU). However, there are very limited data pertaining to the functional consequences of the >450 reported no-synonymous DPYD variants. We developed a DPYD-specific variant classifier (DPYD-Varifier) using machine learning and in vitro functional data for 156 missense DPYD variants. The developed model showed 85% accuracy and outperformed other in silico prediction tools. An examination of feature importance within the model provided additional insight into functional aspects of the DPD protein relevant to 5-FU toxicity. In the absence of clinical data for unstudied variants, prediction tools like DPYD-Varifier have great potential to individualize medicine and improve the clinical decision-making process.
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clinical pharmacogenetics implementation consortium cpic guideline for Dihydropyrimidine Dehydrogenase genotype and fluoropyrimidine dosing 2017 update
Clinical Pharmacology & Therapeutics, 2018Co-Authors: Ursula Amstutz, Howard L. Mcleod, Kelly E Caudle, Teri E Klein, Jesse J Swen, Linda M Henricks, Steven M Offer, Julia M Barbarino, Jan H M Schellens, Robert B. DiasioAbstract:The purpose of this guideline is to provide information for the interpretation of clinical Dihydropyrimidine Dehydrogenase (DPYD) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5-fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost-effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC® ) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/).
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clinical pharmacogenetics implementation consortium guidelines for Dihydropyrimidine Dehydrogenase genotype and fluoropyrimidine dosing
Clinical Pharmacology & Therapeutics, 2013Co-Authors: Kelly E Caudle, Robert B. Diasio, Howard L. Mcleod, Caroline F Thorn, Teri E Klein, Jesse J Swen, Matthias SchwabAbstract:The fluoropyrimidines are the mainstay chemotherapeutic agents for the treatment of many types of cancers. Detoxifying metabolism of fluoropyrimidines requires Dihydropyrimidine Dehydrogenase (DPD, encoded by the DPYD gene), and reduced or absent activity of this enzyme can result in severe, and sometimes fatal, toxicity. We summarize evidence from the published literature supporting this association and provide dosing recommendations for fluoropyrimidines based on DPYD genotype (updates at http://www.pharmgkb.org).
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Dihydropyrimidine Dehydrogenase deficiency in an Indian population
Cancer Chemotherapy and Pharmacology, 2006Co-Authors: Muhammad Wasif Saif, Lori K. Mattison, Tom Carollo, Hany Ezzeldin, Robert B. DiasioAbstract:Background: Dihydropyrimidine Dehydrogenase (DPD) deficiency is prevalent in 3–5% of the Caucasian population; however, the frequency of this pharmacogenetic syndrome in the Indian population and other racial and ethnic groups remains to be elucidated. Patients and methods: We describe an Indian patient who presented to clinic for the treatment of gastric adenocarcinoma with 5-flurouracil (5-FU) therapy who subsequently was diagnosed with DPD deficiency by using the peripheral blood mononuclear cell (PBMC) DPD radioassay. This observation prompted us to examine the data generated from healthy (cancer-free) Indian subjects who were enrolled in a large population study to determine the sensitivity and specificity of the uracil breath test (UraBT) in the detection of DPD deficiency. Thirteen Indian subjects performed the UraBT. UraBT results were confirmed by PBMC DPD radioassay. Results: The Indian cancer patient demonstrated reduced DPD activity (0.11 nmol/min/mg protein) and severe 5-FU toxicities commonly associated with DPD deficiency. Of the 13 Indian subjects [ten men and three women; mean age, 26 years (range: 21–31 years)] enrolled in the UraBT, 12 Indian subjects demonstrated UraBT breath profiles and PBMC DPD activity within the normal range; one Indian subject demonstrated a reduced breath profile and partial DPD deficiency. Conclusions: DPD deficiency is a pharmacogenetic syndrome which is also present in the Indian population. If undiagnosed, the DPD deficiency can lead to death. Future epidemiological studies would be helpful to determine the prevalence of DPD deficiency among racial and ethnic groups, allowing for the optimization of 5-FU chemotherapy.
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Is capecitabine safe in patients with gastrointestinal cancer and Dihydropyrimidine Dehydrogenase deficiency
Clinical Colorectal Cancer, 2006Co-Authors: M. Wasif Saif, Robert B. DiasioAbstract:Patients with cancer with Dihydropyrimidine Dehydrogenase (DPD) deficiency are at significant risk for severe 5-fluorouracil (5-FU) toxicity, including the risk of death. Data regarding the toxicity of capecitabine, an oral fluoropyrimidine, in patients with DPD deficiency are scarce. From 2004 to 2005, 2 patients with gastrointestinal (GI) malignancies (of the pancreas and liver) experienced severe to even life-threatening toxicities during capecitabine therapy, which resulted in death for 1 patient. A DPD enzyme assay was performed as previously defined in our laboratory. Both patients were DPD deficient upon evaluation for toxicity. Capecitabine can lead to severe and sometimes life-threatening toxicities akin to toxicities caused by 5-FU in patients with DPD deficiency. In cases of unexpected severe toxicity during capecitabine treatment, DPD deficiency should be considered. We suggest that capecitabine should not be used in patients with DPD deficiency. Screening should be considered in view of the widespread use of capecitabine and 5-FU, the severe toxicity that can develop in patients with low DPD activity, and the prevalence of the mutation.
A. H. Van Gennip - One of the best experts on this subject based on the ideXlab platform.
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A pivotal role for beta-aminoisobutyric acid and oxidative stress in Dihydropyrimidine Dehydrogenase deficiency?
Nucleosides Nucleotides and Nucleic Acids, 2006Co-Authors: A.b.p. Van Kuilenburg, Nico G.g.m. Abeling, A. E. M. Stroomer, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) constitutes the first step of the pyrimidine degradation pathway in which the pyrimidine bases uracil and thymine are catabolised to β-alanine and β-aminoisobutyric acid (β-AIB), respectively. The mean concentration of β-AIB was approximately 5- to 8-fold lower in urine of patients with a DPD deficiency, when compared to age-matched controls. Comparable levels of 8-hydroxydeoxyguanosine (8-OHdG) were present in urine from controls and DPD patients at the age 2 year, suggesting the presence of increased oxidative stress.
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Dihydropyrimidine Dehydrogenase deficiency presenting at birth
Journal of Inherited Metabolic Disease, 2005Co-Authors: N. A. Al-sanna'a, A.b.p. Van Kuilenburg, T. M. Atrak, M. A. Abdul-jabbar, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) deficiency (McKusick 274270) is a clinically heterogeneous autosomal recessive disorder of pyrimidine metabolism. DPD is the enzyme that catalyses the first and the rate-limiting step in the catabolism of uracil, thymine and the analogue 5-fluorouracil. To date, more than 30 patients have been diagnosed with a complete enzyme deficiency. Here, we describe the fifth case with a complete DPD deficiency presenting at birth with severe neurological abnormalities. The patient was homozygous for the common splice-site mutation IVS14+1G > A.
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Head imaging abnormalities in Dihydropyrimidine Dehydrogenase deficiency.
Journal of Inherited Metabolic Disease, 2004Co-Authors: Gregory M. Enns, A.b.p. Van Kuilenburg, A. J. Barkovich, Melanie A. Manning, T. Sanger, D. R. Witt, A. H. Van GennipAbstract:Summary: Dihydropyrimidine Dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of pyrimidine metabolism. Patients may present with a wide range of neurological symptoms during the first years of life. Head imaging abnormalities have been reported only rarely and include diffuse cerebral atrophy and white-matter hyperintensity. The pathogenesis of the white-matter abnormalities is unknown, although environmental factors and altered energy metabolism may be involved. To further understanding of the spectrum of brain abnormalities associated with DPD deficiency, we report a 17-month-old girl, born to a consanguineous Pakistani couple, who had a history of encephalopathy, prolonged hypoventilation, developmental delay and failure to thrive. Head MRI showed prominent sulci and abnormal T2 prolongation in the cerebral white matter and brainstem. Thus, DPD deficiency may feature prominent brain abnormalities involving the cerebral white matter and brainstem. Anoxic stress may have contributed to the clinical presentation and brain findings in this case. In order to define more clearly the contribution of DPD deficiency to the pathogenesis of these MRI abnormalities, we recommend performing detailed analysis of urine pyrimidine metabolites in patients who have such findings.
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Dihydropyrimidine Dehydrogenase deficiency and acute neurological presentation.
Journal of Inherited Metabolic Disease, 2003Co-Authors: Agata Fiumara, A.b.p. Van Kuilenburg, U. Caruso, C. Nucifora, Elisabetta Marzullo, Rita Barone, Concetta Meli, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) deficiency has been linked to 5-fluorouracil toxicity, but patients may present a wide clinical spectrum. We describe a 1-year-old Tunisian girl with a dramatic onset of neurological symptoms suggesting the possible triggering role of environmental factors.
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Pharmacogenetic and clinical aspects of Dihydropyrimidine Dehydrogenase deficiency.
Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, 2003Co-Authors: Ronney A. De Abreu, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). A deficiency of DPD is increasingly being recognized as the cause of an important pharmacogenetic syndrome. The importance of DPD deficiency in the aetiology of unexpected severe 5FU toxicity has been demonstrated by the fact that, in 39-59% of cases, decreased DPD activity could be detected in peripheral blood mononuclear (PBM) cells. It was observed that 55% of the patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of the patients with a normal DPD activity (P=0.01). Furthermore, toxicity developed significantly earlier in patients with low DPD activity than in patients with normal DPD activity (10.0±7.6 versus 19.1±15.3 days, P
André B.p. Van Kuilenburg - One of the best experts on this subject based on the ideXlab platform.
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Screening for Dihydropyrimidine Dehydrogenase Deficiency: To Do or Not To Do, That's The Question
Cancer Investigation, 2006Co-Authors: André B.p. Van KuilenburgAbstract:The treatment of cancer patients with 5-fluorouracil (5FU)-based chemotherapy can be accompanied by severe and sometimes lethal toxicity. Dihydropyrimidine Dehydrogenase (DPD) plays a pivotal role in the metabolism of 5FU and as such, a deficiency of DPD has been recognized as an important risk factor, predisposing patients to the development of severe 5FU-associated toxicity. To date, screening of patients for the presence of a DPD deficiency prior to the treatment is not yet routinely performed. Taking into account the relatively small impact of adjuvant 5FU-based chemotherapy on survival, patients should be informed about the risks of the therapy and should be offered the possibility of testing for the presence of a DPD deficiency in advance of receiving such treatment.
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Dihydropyrimidine Dehydrogenase and the efficacy and toxicity of 5 fluorouracil
European Journal of Cancer, 2004Co-Authors: André B.p. Van KuilenburgAbstract:The identification of genetic factors associated with either responsiveness or resistance to 5-fluorouracil (5-FU) chemotherapy, as well as genetic factors predisposing patients to the development of severe 5-FU-associated toxicity, is increasingly being recognised as an important field of study. Dihydropyrimidine Dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Although the role of tumoral levels as a prognostic factor for clinical responsiviness has not been firmly established, there is ample evidence that a deficiency of DPD is associated with severe toxicity after the administration of 5-FU. Patients with a partial DPD deficiency have an increased risk of developing grade IV neutropenia. In addition, the onset of toxicity occurred twice as fast compared with patients with a normal DPD activity. To date, 39 different mutations and polymorphisms have been identified in DPYD. The IVS14+1G>A mutation proved to be the most common one and was detected in 24-28% of all patients suffering from severe 5-FU toxicity. Thus, a deficiency of DPD appears to be an important pharmacogenetic syndrome.
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pharmacogenetic and clinical aspects of Dihydropyrimidine Dehydrogenase deficiency
Annals of Clinical Biochemistry, 2003Co-Authors: André B.p. Van Kuilenburg, Ronney A. De Abreu, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). A deficiency of DPD is increasingly being recognized as the cause of an important pharmacogenetic syndrome. The importance of DPD deficiency in the aetiology of unexpected severe 5FU toxicity has been demonstrated by the fact that, in 39-59% of cases, decreased DPD activity could be detected in peripheral blood mononuclear (PBM) cells. It was observed that 55% of the patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of the patients with a normal DPD activity (P = 0.01). Furthermore, toxicity developed significantly earlier in patients with low DPD activity than in patients with normal DPD activity (10.0 +/- 7.6 versus 19.1 +/- 15.3 days, P A), one nonsense mutation (E386X), four missense mutations (M166V, V335L, I560S, D949V) and five polymorphisms (C29R, R21Q, S534N, I543V, V732I). Considering the common use of 5FU in the treatment of cancer patients, the severe 5FU-related toxicities in patients with a low DPD activity and the high prevalence of the IVS14 + 1G-->A mutation, analysis of the DPD activity in PBM cells or screening for the IVS14 + 1G-->A mutation should be routinely carried out prior to the start of treatment with 5FU.
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high prevalence of the ivs14 1g a mutation in the Dihydropyrimidine Dehydrogenase gene of patients with severe 5 fluorouracil associated toxicity
Pharmacogenetics, 2002Co-Authors: André B.p. Van Kuilenburg, Lida Zoetekouw, Rutger Meinsma, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU) and a DPD deficiency is increasingly being recognized as an important pharmacogenetic factor in the aetiology of severe 5FU-associated toxicity. In this study, we evaluated the DPD
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Dihydropyrimidine Dehydrogenase dpd deficiency novel mutations in the dpd gene
Advances in Experimental Medicine and Biology, 2002Co-Authors: André B.p. Van Kuilenburg, Rutger Meinsma, Janet Haasjes, Hans R. Waterham, Peter Vrelem, A. H. Van GennipAbstract:Dihydropyrimidine Dehydrogenase (DPD, EC 1.3.1.2) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases and it catalyzes the reduction of uracil and thymine to 5,6-dihydrouracil and 5,6-dihydrothymine, respectively. In children, a deficiency of DPD is often accompanied by a neurological disorder but a considerable variation in the clinical presentation among these patients has been reported1. In these patients, a large accumulation of uracil and thymine has been detected in urine, blood and in cerebrospinal fluid whereas no activity of DPD could be detected in fibroblasts and mononuclear cells . The detection of more than 30 patients of various nationalities with a (partial) DPD deficiency within 15 years in The Netherlands alone suggest that this type of inborn error is less rare than previously assumed 1, 2 The recent cloning of the cDNA coding for human DPD and the sequence of the entire human DPD gene3 (DPYD) has allowed the detection of the defects at the molecular level. Identification of disease-causing mutations in the DPD gene will allow rapid pre-screening of patients at risk.
Carlo R Largiader - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine Dehydrogenase gene as a major predictor of severe 5 fluorouracil toxicity
Pharmacogenomics, 2011Co-Authors: Ursula Amstutz, Tanja K Froehlich, Carlo R LargiaderAbstract:The importance of polymorphisms in the Dihydropyrimidine Dehydrogenase (DPD) gene (DPYD) for the prediction of severe toxicity in 5-fluorouracil (5-FU) based chemotherapy has been controversially debated. As a key enzyme in the catabolism of 5-FU, DPD is the top candidate for pharmacogenetic studies on 5-FU toxicity, since a reduced DPD activity is thought to result in an increased half-life of the drug, and thus, an increased risk of toxicity. Here, we review the current knowledge on well-known and frequently studied DPYD variants such as the c.1905+1G>A splice site variant, as well as the recent discoveries of important functional variation in the noncoding regions of DPYD. We also outline future directions that are needed to further improve the risk assessment of 5-FU toxicity, in particular with respect to metabolic profiling and in the context of different combination therapeutic regimens, in which 5-FU is used today.
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Dihydropyrimidine Dehydrogenase gene variation and severe 5 fluorouracil toxicity a haplotype assessment
Pharmacogenomics, 2009Co-Authors: Ursula Amstutz, Simone Farese, Stefan Aebi, Carlo R LargiaderAbstract:Aims: The importance of polymorphisms in the Dihydropyrimidine Dehydrogenase gene (DPYD) for the prediction of severe toxicity in 5-fluorouracil (5-FU)-based chemotherapy is still unclear. This study aims to assess the predictive value of DPYD variation with respect to previously described DPYD variants for 5-FU toxicity. It represents the first analysis of the gene at the haplotype level, also capturing potentially important genetic variation located outside the coding regions of DPYD. Materials & methods: The entire coding sequence and exon-flanking intronic regions of DPYD were sequenced in 111 cancer patients receiving fluoropyrimidine-based chemotherapy. DPYD haplotypes were inferred and their associations with severe 5-FU toxicity were assessed. Results: None of the previously described deleterious variants (IVS14+1G>A, c.2846A>T and c.1679T>G) were detected in 24 patients who experienced severe 5-FU toxicity. A potential association was observed between a haplotype containing three novel intronic p...
Wafik S Eldeiry - One of the best experts on this subject based on the ideXlab platform.
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abstract 3706 p53 represses pyrimidine catabolic gene Dihydropyrimidine Dehydrogenase dpyd expression following thymidylate synthase ts inhibition
Cancer Research, 2016Co-Authors: Prashanth Gokare, Niklas Finnberg, Jenny Dai, Maureen E Murphy, Wafik S EldeiryAbstract:Nucleotide catabolism by cancer cells can influence malignant behavior and intrinsic resistance to therapy. The rate-limiting enzyme in the pyrimidine catabolic pathway, Dihydropyrimidine Dehydrogenase (DPYD) contributes to the pharmacokinetics of fluorouracil (5-FU). Using in silico/chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU. Histone H3K9 acetylation marks at the DPYD promoter is diminished concomitantly with reduced expression of DPYD mRNA and protein in a p53-dependent manner. Notably we find that the P72 allele of p53 suppresses DPYD expression more than the R72 p53 allele following 5-FU treatment in mouse embryo fibroblasts. Mechanistic studies reveal inhibition of DPYD expression by p53 is augmented following thymidylate synthase (TS) inhibition by 5-FU, methotrexate (MTX), raltitrexed and siRNA in cancer cells in vitro as well as in mice in vivo. DPYD repression by p53 is dependent on DNA-PK and ATM-signaling since pharmacologic targeting of these kinases reverses the transcriptional repression of DPYD by p53. Mice lacking p53 in their livers have increased conversion of 5-FU to 5-FUH2 in plasma and elicit a diminished 5-FU therapeutic response in syngeneic colorectal tumor xenografts as compared to littermates with an intact p53 allele consistent with increased DPYD-activity. Our data suggest that p53 plays an important role in controlling pyrimidine catabolism through its ability to regulate DPYD, particularly following metabolic stress imposed by nucleotide imbalance. The findings have implications for the toxicity and efficacy of the cancer therapeutic 5-fluorouracil. Citation Format: Prashanth Ravishankar Gokare, Niklas Finnberg, Jenny Dai, Maureen Murphy, Wafik El-Deiry. p53 represses pyrimidine catabolic gene Dihydropyrimidine Dehydrogenase (DPYD) expression following thymidylate synthase (TS) inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3706.
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abstract pr03 p53 inhibits the expression of the pyrimidine catabolic gene Dihydropyrimidine Dehydrogenase dpyd
Molecular Cancer Research, 2016Co-Authors: Prashanth Gokare, Niklas Finnberg, Jenny Dai, Wafik S EldeiryAbstract:Fluorouracil (5-FU) a widely used chemotherapeutic drug whose unpredictable pharmacokinetics is controlled by the pyrimidine catabolic gene Dihydropyrimidine Dehydrogenase (DPYD), that has recently also been shown to be a gatekeeper of the epithelial-to-mesenchymal transition (EMT) in breast cancer. Relatively little is known about the transcriptional control of DPYD and here we show for the first time an interaction between p53 and DPYD (involved in catabolism of pyrimidines as well as 5-FU) where p53 represses both the base-line expression of DPYD and that following 5-FU administration in vitro and in vivo. This mechanism affects the catabolic conversion of 5-FU to 5-FUH2 in mice in vivo. Using an in-silico approach we also identified several putative p53 binding sites (P53DBS) in and around ~20Kb upstream and downstream of the mouse DPYD gene. In-vivo ChIP from mice livers identified a key p53DBS binding site downstream (chr3: 119451237-11941257) of the gene to which p53 binds to at about 1.8 ± 0.05 fold over untreated control following a single IV bolus of 5-FU (150 mg/kg bw). Interestingly DPYD mRNA and protein levels were decreased by 1.8 and 1.5 fold respectively (P Citation Format: Prashanth Ravishankar Gokare, Niklas Finnberg, Jenny Dai, Wafik El-Deiry. P53 inhibits the expression of the pyrimidine catabolic gene Dihydropyrimidine Dehydrogenase (DPYD). [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr PR03.