title: Combined interaction of multi-locus genetic polymorphisms in cytarabine arabinoside metabolic pathway on clinical outcomes in adult acute myeloid leukaemia (AML) patients.
abstract: Cytarabine arabinoside (ara-C) is the key agent for treating acute myeloid leukaemia (AML). Here, we genotyped 139 single nucleotide polymorphisms (SNPs) within the ara-C transport and metabolic pathway using the Illumina Golden Gate Assay in 97 patients with previously non-treated de novo AML other than M3. DCK rs4694362 (CC genotype) was a significant poor prognostic factor for overall survival (OS) (hazard ratio [HR], 33.202 [95% confidence interval (CI), 4.937-223.273], P<0.0001, P(Bonferroni)=0.017). SLC29A1 rs3734703 (AA or AC genotype) in combination with TYMS rs2612100 (AA genotype) was significantly associated with shorter relapse free survival (RFS) (HR, 17.630 [95% CI, 4.829-64.369], P<0.0001, P(Bonferroni)=0.021). These SNPs showed moderate or large inter ethnic divergence in allele frequencies from African or Caucasian populations. The results of our study suggest that a single SNP and SNP-SNP interactions may help to predict the drug response and provide a guide in developing individualised chemotherapy for AML patients receiving ara-C based chemotherapy.
authors.affiliation: College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, South Korea.
authors.forename: Kyung Im
authors.initials: KI
authors.lastname: Kim
authors.forename: Ik-Soo
authors.initials: IS
authors.lastname: Huh
authors.forename: In-Wha
authors.initials: IW
authors.lastname: Kim
authors.forename: Taesung
authors.initials: T
authors.lastname: Park
authors.forename: Kwang-Sung
authors.initials: KS
authors.lastname: Ahn
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Oh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D058885:Multilocus Sequence Typing; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D003561:Cytarabine