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

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-Stransferase 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 postinduction 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 doublestrand breaks (etoposide, daunomycin), compared with antimetabolite (fludarabine, cytarabine) based therapy. In contrast, RAD51 G135C and the GSTM1 deletion polymorphism did not influence outcome of AML therapy in our study population.

Glutathione S-transferase Gene Polymorphisms and Susceptibility to Acute Myeloid Leukemia: Meta-analyses

“…The genetic polymorphisms that have been described for multiple genes associated with DNA repair may contribute to the reported variation in the ability to detoxify (5), which could explain the mechanism of individual differences in susceptibility to AML. The glutathione S-transferases (GSTs) are a family of Phase II enzymes that are involved in the detoxification of xenobiotics.…”

The Association of the DNA Repair Genes with Acute Myeloid Leukemia: The Susceptibility and the Outcome After Therapy

“…Other reports found increased frequency of the RAD51 135C allele in t-AML patients compared with controls (Seedhouse et al, 2004), suggesting an effect of RAD51 over-expression during leukemogenesis induced by chemotherapy or radiotherapy. According to Bhatla et al (2008) RAD51 gene polymorphism did not influence the outcome of AML therapy in the study of de novo AML patients. On the contrary, Liu et al (2008) concluded that RAD51 gene polymorphism was significantly related to response to therapy, adverse effects, and prognosis of AML and reported that detection of the RAD51 gene polymorphism genotypes may be useful in selecting individual chemotherapy regimens for patients with AML.…”

135G/C polymorphism in the RAD51 gene and acute myeloid leukemia risk: a meta-analysis

“…Through screening the title and reading the abstract and the entire article, 6 eligible articles were selected for this meta-analysis (Seedhouse et al, 2004;Rollinson et al, 2007;Voso et al, 2007;Bhatla et al, 2008;Hamdy et al, 2011;Liu et al, 2011). The flow chart for the study selection is summarized in Figure 1, including a total of 1432 cases and 2750 controls.…”

“…The flow chart for the study selection is summarized in Figure 1, including a total of 1432 cases and 2750 controls. There were 4 studies (Seedhouse et al, 2004;Rollinson et al, 2007;Voso et al, 2007;Hamdy et al, 2011) of Caucasian descent, 1 study (Liu et al, 2011) of Asian descent, and one study (Bhatla et al, 2008) of mixed descent. The HWE test was performed on genotype distribution of the controls and all were in agreement with HWE.…”