title: Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines.
abstract: Dihydropyrimidine dehydrogenase (DPD) is a critical determinant of 5-fluorouracil pharmacology, and reduced activity of DPD as a result of deleterious polymorphisms in the gene encoding DPD (DPYD) can result in severe treatment-related toxicity. Dosing recommendations to individualize treatment have been provided for three DPYD variants (DPYD*2A, c.2846A>T, and c.1679T>G). A fourth variant, c.1129-5923C>G/HapB3, has been shown to increase the risk of fluoropyrimidine-associated toxicity, but little is known about the functional effects of this variant.
  
  
  
  By performing a large retrospective screen for DPYD variants, we identified three patients who were homozygous for c.1129-5923C>G/HapB3. We describe their clinical course of treatment and analyzed DPD activity and DPYD gene expression, to provide insight into the phenotypic effects of c.1129-5923C>G/HapB3.
  
  
  
  DPD activity could be measured in two patients and was 4.1 and 5.4 nmol/mg/h (DPD activity 41 and 55 % compared to controls, respectively). The fluoropyrimidine dose had to be reduced during treatment in both patients. In line with partial DPD deficiency in both patients, sequence analysis of DPD cDNA demonstrated a normal-sized (wild type) cDNA fragment of 486 bp, as well as a larger-sized (mutant) 530-bp fragment containing an aberrant 44-bp insertion in intron 10. Patient three tolerated treatment well, but DPD activity measurement was not possible as the patient had deceased at the time of performing the study.
  
  
  
  The presented functional and clinical data indicate that the c.1129-5923C>G variant is both functionally and clinically relevant, and support an upfront dose reduction of the fluoropyrimidine starting dose in patients carrying c.1129-5923C>G homozygously.
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. didier.meulendijks@gmail.com.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. didier.meulendijks@gmail.com.|Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, The Netherlands. didier.meulendijks@gmail.com.
authors.forename: Didier
authors.initials: D
authors.lastname: Meulendijks
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Henricks
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Bart A W
authors.initials: BA
authors.lastname: Jacobs
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Abidin
authors.initials: A
authors.lastname: Aliev
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Rozeman
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Meijer
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands.
authors.forename: Hiltje
authors.initials: H
authors.lastname: de Graaf
authors.affiliation: Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Cats
authors.affiliation: Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D000069287:Capecitabine / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D018076:DNA, Complementary / Q000235:genetics; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D057285:Precision Medicine; D012189:Retrospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D018076:DNA, Complementary; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil
keywords: 5-Fluorouracil; Capecitabine; DPYD; Dihydropyrimidine dehydrogenase; Fluoropyrimidines; Toxicity