1. ¹Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
2. ²Operations Center, Children's Oncology Group, Arcadia, CA, USA
3. ³Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
4. ⁴Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, WA, USA
5. ⁵Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

Correspondence: Dr D Bhatla, Division of Hematology/Oncology, Cincinnati Children's Hospital and Medical Center, ML 7013, 3333, Burnet Avenue, Cincinnati, OH 45229, USA. E-mail: deepika.bhatla@cchmc.org

Received 9 May 2007; Revised 18 September 2007; Accepted 19 September 2007; Published online 22 November 2007.

Abstract

Polymorphisms of DNA repair genes RAD51 and XRCC3 increase susceptibility to acute myeloid leukemia (AML) in adults, an effect enhanced by deletion of the glutathione-S-transferase M1 (GSTM1) gene. In this study, we genotyped 452 children with de novo AML treated on CCG protocols 2941 and 2961 and compared genotype frequencies with those of normal blood donors, and analyzed the impact of genotype on outcome of therapy. XRCC3 Thr241Met, RAD51 G135C and GSTM1 genotypes did not increase susceptibility to AML when assessed singly. In contrast, when XRCC3 and RAD51 genotypes were examined together a significant increase in susceptibility to AML was seen in children with variant alleles. Analysis of outcome of therapy showed that patients heterozygous for the XRCC3 Thr241Met allele had improved post-induction disease-free survival compared to children homozygous for the major or minor allele, each of whom had similar outcomes. Improved survival was due to reduced relapse in the heterozygous children, and this effect was most marked in children randomized to therapy likely to generate DNA double-strand breaks (etoposide, daunomycin), compared with anti-metabolite (fludarabine, cytarabine) based therapy. In contrast, RAD51 G135C and the GSTM1 deletion polymorphism did not influence outcome of AML therapy in our study population.