title: Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10(-6)) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.forename: Joel A
authors.initials: JA
authors.lastname: Mefford
authors.forename: Natasha
authors.initials: N
authors.lastname: Singh
authors.forename: Mary-Elizabeth
authors.initials: ME
authors.lastname: Percival
authors.forename: Adrian
authors.initials: A
authors.lastname: Stecula
authors.forename: Kuo
authors.initials: K
authors.lastname: Yang
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
authors.forename: Charalambos
authors.initials: C
authors.lastname: Andreadis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002066:Busulfan / Q000627:therapeutic use; D002874:Chromosome Mapping; D003561:Cytarabine / Q000627:therapeutic use; D004247:DNA / Q000235:genetics; D018572:Disease-Free Survival; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D056426:Genetic Loci; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012074:Remission Induction; D055815:Young Adult
chemical_list: D002066:Busulfan; D003561:Cytarabine; D004247:DNA; D005047:Etoposide; D005982:Glutathione Transferase; D026901:Membrane Transport Proteins; C065171:cif nucleoside transporter; C524366:GSTM5 protein, human