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Acute Leukemias

DNA repair polymorphisms and outcome of chemotherapy for acute myelogenous leukemia: a report from the Children's Oncology Group

Leukemia volume 22, pages 265–272 (2008)Cite this article

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.

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Acknowledgements

This work was supported by R01CA93552-01 (SMD), R21 CA10262-01, R01 CA114563-01, (SM) and COG Grant CA 98543. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm

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Authors and Affiliations

  1. Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    D Bhatla, P A Mehta, K Deal, J Elliott, H Geiger, J P Perentesis & S M Davies

  2. Operations Center, Children's Oncology Group, Arcadia, CA, USA

    R B Gerbing

  3. Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA

    T A Alonzo

  4. Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, WA, USA

    S Meshinchi

  5. Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    B J Lange

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  1. D Bhatla
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Correspondence to D Bhatla.

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Bhatla, D., Gerbing, R., Alonzo, T. et al. DNA repair polymorphisms and outcome of chemotherapy for acute myelogenous leukemia: a report from the Children's Oncology Group. Leukemia 22, 265–272 (2008). https://doi.org/10.1038/sj.leu.2405000

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