title: Novel deoxycytidine kinase gene polymorphisms: a population screening study in Caucasian healthy volunteers.
abstract: BACKGROUND
  Deoxycytidine kinase (DCK) is the rate-limiting enzyme of the intracellular phosphorylation of nucleoside anticancer drugs, including gemcitabine and beta-arabinofuranosylcytosine, to their active triphosphates. This study was performed to assess the occurrence and frequency of DCK polymorphisms in a predominantly Caucasian population and to choose candidate polymorphisms for subsequent functionality studies.
  
  
  METHODS
  All seven DCK exons and the promoter region were sequenced from 100 healthy volunteers (79 females and 21 males). With respect to ethnicity, the study cohort comprised 93 Caucasian, one Asian, one African, and five mixed-race individuals.
  
  
  RESULTS
  Six novel single nucleotide polymorphisms (SNPs) were found (-243G>T, -135G>C, 261G>A, 364C>T, 727A>C, IVS6+41T>A). Two SNPs are nonsynonymous and lead to changes in the amino acid sequence [C364T in exon 3 (P121S) and A727C in exon 6 (K242Q)]. The presence of the linked promoter polymorphism -360C>G/-201C>T was confirmed in Caucasians, but was less frequent than what has been reported from Asians (allele frequencies 2 versus 15.6%). The most prevalent haplotype was the wild-type plus IVS6+41TT (85.8%). This study found novel DCK polymorphisms, including nonsynonymous SNPs, in exons 3 and 6. A comparison of the data obtained in this study with those reported in a previous study on Asians [Shi et al. (2004) Pharmacogenetics 14:759-768] illustrates marked inter-ethnic differences in the occurrence and frequency of DCK polymorphisms.
  
  
  CONCLUSIONS
  The higher allelic frequency of the promoter polymorphism -C360G/-C201T in Asians than in Caucasians might predispose Asians to nucleoside drug-associated toxicity. These data will be used to assess the effect of DCK candidate SNPs (promoter, exons 3 and 6) in patients receiving gemcitabine anticancer treatment.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. apmsj@slz.nl
authors.forename: M
authors.initials: M
authors.lastname: Joerger
authors.forename: T M
authors.initials: TM
authors.lastname: Bosch
authors.forename: V D
authors.initials: VD
authors.lastname: Doodeman
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: P H M
authors.initials: PH
authors.lastname: Smits
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D003842:Deoxycytidine Kinase / Q000235:genetics*; D005260:Female; D005828:Genetics, Population; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D003842:Deoxycytidine Kinase