Polymorphisms in the glutathione s-transferase genes and treatment outcomes in acute myeloid leukemia
Weiss, Joli Renee
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Concordance between germline and tumor DNA samples were investigated to determine the feasibility of using stored tumor samples as a source of genomic DNA for acute myeloid leukemia (AML) pharmacogenetic studies. We compared genotypes determined in DNA extracted from paired pre-treatment bone marrow and buccal samples from 80 adult AML patients. Paired samples were genotyped for polymorphisms in CYP3A4, CYP2C8, CDA, GSTP1, CAT, MnSOD, GSTT1, GSTA1, GSTM1, GPX1, MDR1, MRP1, BCRP, MGMT, XPD, and XRCC1 . Kappa statistics for the paired samples ranged between 0.94 and 1.00, indicating excellent agreement. Based on these data, genotypes derived from archived AML samples are not likely to differ from those from genomic DNA, and archived bone marrow samples may be useful for the conduct of retrospective pharmacogenetic studies. Archived pre-treatment bone marrow samples were then utilized to determine glutathione s-transferase ( GST ) genotypes ( GSTM1, GSTT1, GSTA1, GSTP1 ) in two populations of adult AML patients to examine response to therapy. The first study included patients (n=200) aged 56-88 who were treated with standard doses of cytarabine and daunorubicin in two SWOG clinical trials. The second study included patients (n=273) aged 20-85 treated with standard protocols of cytarabine and an anthracycline at Roswell Park Cancer Institute, Buffalo, NY between 1994 and 2006. In both studies we observed no GST genotype to be significantly associated with response to induction chemotherapy, overall survival (OS), or relapse-free survival (RFS). We did observe a trend for decreased risk of grade 3 or higher toxicity in any one or more organ systems for patients with null or variant genotypes compared to patients with grade 0 to 2 toxicities in all organ systems. GSTM1 null and GSTM1/T1 double null genotypes were both associated with a significant decrease in risk of developing a grade 3 or higher event (aOR=0.49, 95% CI=0.29-0.85 and aOR=0.36, 95% CI=0.14-0.89, respectively). Our results indicate that while the GSTs may not play a significant role in survival outcomes, they may play an important role in modifying toxicities to therapy. Further research into the role of the GSTs and development of toxicities after induction therapy are warranted.