4552

MTRR

MSR|cblE;5-methyltetrahydrofolate-homocysteine methyltransferase reductase;MTRR;5-methyltetrahydrofolate-homocysteine methyltransferase reductase

[methionine synthase]-cobalamin methyltransferase (cob(II)alamin reducing)|methionine synthase reductase|methionine synthase reductase, mitochondrial

5p15.31

protein-coding

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Genetic polymorphisms in the folate metabolic pathway may contribute to the susceptibility to childhood ALL because they affect the DNA synthesis, methylation and repair. We analysed common genetic polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MS) and methionine synthase reductase (MTRR) in 68 childrenwith ALL and 258 healthy controls to investigate their influence on the risk forALL. No significant differences in frequencies of separate polymorphisms were observed between both groups. Combined MTHFR 677CT/TT and MS 2756AG/GG genotypesshowed a nonsignificant tendency to reduce the risk for ALL 2.24-fold (CI: 0.191- 1.037, P: 0.061). The risk was significantly reduced in carriers of combined MTHFR 677CT/TT, MS 2756AG/GG and MTRR 66AG/GG genotypes (OR: 0.312; CI: 0.107 - 0.907; P: 0.032). Our results suggest that gene - gene interactions that may decrease the methylation capacity might have a protective effect on the risk forchildhood ALL.

BACKGROUND: Recent studies suggest that polymorphisms in genes encoding enzymes involved in drug detoxification and metabolism may influence disease outcome in pediatric acute lymphoblastic leukemia (ALL). We sought to extend current knowledge by using standard and novel statistical methodology to examine polymorphic variants of genes and relapse risk, toxicity, and drug dose deliveryin standard risk ALL. PROCEDURE: We genotyped and abstracted chemotherapy drug dose data from treatment roadmaps on 557 patients on the children's cancer GroupALL study, CCG-1891. Fourteen common polymorphisms in genes involved in folate metabolism and/or phase I and II drug detoxification were evaluated individuallyand clique-finding methodology was employed for detection of significant gene-gene interactions. RESULTS: After controlling for known risk factors, polymorphisms in four genes: GSTP1*B (HR = 1.94, P = 0.047), MTHFR (HR = 1.61, P= 0.034), MTRR (HR = 1.95, P = 0.01), and TS (3R/4R, HR = 3.69, P = 0.007) were found to significantly increase relapse risk. One gene-gene pair, MTRR A/G and GSTM1 null genotype, significantly increased the risk of relapse after correction for multiple comparisons (P = 0.012). Multiple polymorphisms were associated with various toxicities and there was no significant difference in dose of chemotherapy delivered by genotypes. CONCLUSIONS: These data suggest that various polymorphisms play a role in relapse risk and toxicity during childhood ALL therapy and that genotype does not play a role in adjustment of drug dose administered. Additionally, gene-gene interactions may increase the risk of relapse in childhood ALL and the clique method may have utility in further exploring these interactions. childhood ALL therapy.#CI- Copyright (c) 2011 Wiley Periodicals, Inc.