Cytidine deaminase polymorphisms and worse treatment response in normal karyotype AML.
The cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of the cytarabine (AraC) into a 1-β-D-arabinofuranosyluracil (AraU), an inactive metabolite that plays a crucial role in lowering the amount of AraC, a key chemotherapeutic drug, in the treatment of patients with acute myeloid leukemia (AML). In this study, we hypothesized that CDA polymorphisms were associated with the AraC metabolism for AML treatment and/or related clinical phenotypes. We analyzed 16 polymorphisms of CDA among 50 normal karyotype AML (NK-AML) patients, 45 abnormal karyotype AML (AK-AML) patients and 241 normal controls (NC). Several polymorphisms and haplotypes, rs532545, rs2072671, rs471760, rs4655226, rs818194 and CDA-ht3, were found to have a strong correlation with NK-AML compared with NC and these polymorphisms also revealed strong linkage disequilibrium with each other. Among them, rs2072671 (79A>C), which is located in a coding region and the resultant amino acid change K27Q, showed significant associations with NK-AML compared with NC (P=0.009 and odds ratio=2.44 in the dominant model). The AC and CC genotypes of rs2072671 (79A>C) were significantly correlated with shorter overall survival rates (P=0.03, hazard ratio=1.84) and first complete remission duration (P=0.007, hazard ratio=3.24) compared with the AA genotype in the NK-AML patients. Our results indicate that rs2072671 in CDA may be an important prognostic marker in NK-AML patients.
Department of Life Science, Sogang University, Seoul, Republic of Korea.|Department of Genetic Epidemiology, SNP Genetics, Seoul, Republic of Korea.
Lyoung
L
Hyo Kim
Department of Genetic Epidemiology, SNP Genetics, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Hyun
H
Sub Cheong
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Youngil
Y
Koh
Functional Genome Institute, PDXen Biosystem, Seoul, Republic of Korea.
Kwang-Sung
KS
Ahn
Cancer Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Chansu
C
Lee
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
Hyung-Lae
HL
Kim
Department of Life Science, Sogang University, Seoul, Republic of Korea.|Department of Genetic Epidemiology, SNP Genetics, Seoul, Republic of Korea.
Hyoung
H
Doo Shin
Cancer Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Sung-Soo
SS
Yoon
D000293:Adolescent; D000328:Adult; D000368:Aged; D003561:Cytarabine / Q000008:administration & dosage*; D003564:Cytidine Deaminase / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006239:Haplotypes; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D015996:Survival Rate
D003561:Cytarabine; D003564:Cytidine Deaminase