Single Nucleotide Polymorphisms of DNA Synthetic and Repair Enzymes and Risk of Childhood Acute Lymphoblastic Leukemia.

Although the outcome of children with acute lymphoblastic leukemia (ALL) has been improving, the origin of this disease is still unknown. It is likely that individual genetic susceptibility and environmental exposure play a role in carcinogenesis. To maintain normal hematopoiesis, DNA synthesis and repair systems need to be intact. Folate metabolism, producing purines and pyrimidines, is the source of nucleotides while base excision and nucleotide excision repair enzymes, i.e. XRCC1 and XPD, have important roles in protection of DNA damage. Single nucleotide polymorphisms (SNPs) of enzymes involving these processes alter their enzymatic structures and functions. We hypothesized that SNPs of folate metabolic enzymes including methylenetetrahydrofolate reductase (MTHFR 677 C>T; 1298 A>C), methionine synthase (MS 2756 A>G), and tandem repeats of thymidylate synthase (TS 2R or 3R) and of DNA repair enzymes (XRCC1 26304 C>T; 27466 G>A; 28152 G>A and XPD 23591 G>A; 35931 A>C) could effect the risk of ALL in children. We performed genotyping of these SNPs in 108 ALL and 317 normal controls by using PCR RFLP method. Genotype frequencies of folate metabolic enzymes SNPs were not different between cases and controls. However, TS 2R allele showed a trend to decrease risk of ALL (OR=0.66; 95% CI 0.41–1.07). We observed a 4.5 fold reduction in the risk of ALL in individuals with the XRCC1 26304 TT genotype (OR=0.22; 95% CI 0.5–0.96). XRCC1 26304 T allele showed a protective effect to this disease (OR=0.67; 95% CI 0.47–0.97). In contrast, individuals with XRCC1 28152 A allele had an increased risk of ALL (OR=1.67; 95% CI 1.2–2.33) compared to those with G allele. XRCC1 28152 GA and GA+AA genotypes were significantly higher among patients with ALL compared to controls (OR=2.17; 95% CI 1.37–3.45 and OR=2.18; 95%CI 1.38–3.42). No association between genotype or allele frequencies of both XPD SNPs and risk of ALL was shown in this study. In conclusion, our data demonstrated that SNPs of DNA repair enzymes (XRCC1 26304 C>T and 28152 G>A) but not folate-dependent DNA synthetic enzymes may influence risk of childhood ALL.