title: Twenty novel genetic variations and haplotype structures of the DCK gene encoding human deoxycytidine kinase (dCK).
abstract: Deoxycytidine kinase (dCK) is a rate-limiting enzyme in the activation of nucleoside anticancer drugs, such as gemcitabine and cytarabine (Ara-C), to their active metabolites. In this study, the 5'-flanking region, 7 exons and their flanking introns of DCK were comprehensively screened for genetic variations in 256 Japanese cancer patients administered gemcitabine. Twenty-nine genetic variations, including twenty novel ones, were found: 11 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 1 in the coding exon, 9 in the 3'-UTR, and 7 in the introns. The novel variations included -1110C>T, -757G>A, -639C>T, -465G>A, -402T>C, -224C>A, -199C>G, IVS1+38G>T, IVS2+78_+83delTTTTTC, IVS3-9C>T, IVS4+12T>C, IVS5+39T>C, 1357A>G, 1545A>T, 1572delA, 1736G>A, 1749G>A, 1838T>C, 1889G>A, and 2048A>T. The frequencies were 0.01 for IVS2+78_ +83delTTTTTC, 0.008 for -402T>C, 0.006 for -639C>T and IVS4+12T>C, 0.004 for -757G>A and 1572delA, and 0.002 for the other 14 variations. A known nonsynonymous SNP 364C>T (Pro122Ser) was detected at a 0.061 frequency. Using the detected polymorphisms, linkage disequilibrium analysis was performed, and 24 haplotypes were identified or inferred. Our findings suggest considerable ethnic differences in genetic variations of DCK and provide fundamental and useful information for genotyping DCK in the Japanese and probably other Asian populations.
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan. kim@nihs.go.jp
authors.forename: Su-Ryang
authors.initials: SR
authors.lastname: Kim
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.forename: Emiko
authors.initials: E
authors.lastname: Sugiyama
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Hideki
authors.initials: H
authors.lastname: Ueno
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Chigusa
authors.initials: C
authors.lastname: Morizane
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007564:Japan; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine