Twenty novel genetic variations and haplotype structures of the DCK gene encoding human deoxycytidine kinase (dCK).
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.
Kim
Su-Ryang
SR
Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan. kim@nihs.go.jp
Saito
Yoshiro
Y
Maekawa
Keiko
K
Sugiyama
Emiko
E
Kaniwa
Nahoko
N
Ueno
Hideki
H
Okusaka
Takuji
T
Ikeda
Masafumi
M
Morizane
Chigusa
C
Yamamoto
Noboru
N
Yoshida
Teruhiko
T
Kamatani
Naoyuki
N
Furuse
Junji
J
Ishii
Hiroshi
H
Saijo
Nagahiro
N
Ozawa
Shogo
S
Sawada
Jun-Ichi
J
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
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine