Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio.
Despite the growing evidence that dihydropyrimidine dehydrogenase deficiency (DPD, encoded by the DPYD gene) confers a higher risk of developing severe toxicity, most patients are not screened for DPD deficiency before fluoropyrimidine treatment. We report here the genetic and phenotypic analyses of DPD in a family related to a patient who died after a first cycle of 5-fluorouracil and in 15 additional retrospective patients having a partial DPD deficiency (as measured by plasma dihydrouracil/uracil ratio). The patient with lethal toxicity was found to be a compound heterozygote for two DPYD mutations: a novel 8-bp duplication (c.168_175dupGAATAATT, p.Phe59Ter) and c.1679T>G (Ile560Ser). The patient's dihydrouracil/uracil ratio indicates complete DPD deficiency. The novel mutation was found in two members of the patient's family. Deleterious DPYD mutations were identified in 9 out of the 15 patients. The relationship between genotype and dihydrouracil/uracil values in the 22 patients of the present study was significant (P = 0.01).
Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.|EA4553, Univ. Toulouse III Paul Sabatier, Toulouse, France.
F
F
Thomas
Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.|EA4553, Univ. Toulouse III Paul Sabatier, Toulouse, France.
I
I
Hennebelle
Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.|EA4553, Univ. Toulouse III Paul Sabatier, Toulouse, France.
C
C
Delmas
Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.|EA4553, Univ. Toulouse III Paul Sabatier, Toulouse, France.
I
I
Lochon
UJF Grenoble I, University Hospital Albert Michallon, Department of Pharmacy, Grenoble, France.
C
C
Dhelens
Institut Daniel Hollard, Department of Medical Oncology, Grenoble, France.
C
C
Garnier Tixidre
University Hospital Albert Michallon, Medical Intensive Care Unit, UJF Grenoble I, Grenoble, France.
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A
Bonadona
Centre Oscar Lambret, Department of Medical Oncology, Lille, France.
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N
Penel
Institut Paoli Calmettes, Department of Medical Oncology, Marseille, France.
A
A
Goncalves
EA4553, Univ. Toulouse III Paul Sabatier, Toulouse, France.|Institut Claudius Regaud, IUCT-O, Department of Medical Oncology, Toulouse, France.
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JP
Delord
Institut Claudius Regaud, IUCT-O, Laboratory of Oncogenetics, Toulouse, France.
C
C
Toulas
Institut Claudius Regaud, IUCT-O, Department of Pharmacology, Toulouse, France.|EA4553, Univ. Toulouse III Paul Sabatier, Toulouse, France.
E
E
Chatelut
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D001711:Biotransformation; D004247:DNA / Q000235:genetics*; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000175:diagnosis* / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005190:Family; D017809:Fatal Outcome; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects; D020440:Gene Duplication; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D014498:Uracil / Q000031:analogs & derivatives* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; C007419:dihydrouracil; D014498:Uracil; D004247:DNA; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil