Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia

J Hum Genet. 2013 Jun;58(6):353-61. doi: 10.1038/jhg.2013.38. Epub 2013 May 16.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Busulfan / therapeutic use
  • Chromosome Mapping
  • Cytarabine / therapeutic use
  • DNA / genetics
  • Disease-Free Survival
  • Etoposide / therapeutic use
  • Female
  • Follow-Up Studies
  • Genetic Loci
  • Genotype
  • Glutathione Transferase / genetics
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics*
  • Male
  • Membrane Transport Proteins / genetics
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Proportional Hazards Models
  • Remission Induction
  • Young Adult

Substances

  • Membrane Transport Proteins
  • cif nucleoside transporter
  • Cytarabine
  • Etoposide
  • DNA
  • Glutathione Transferase
  • glutathione S-transferase M1
  • glutathione S-transferase M5, human
  • Busulfan