Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia

Abstract

The prediction of high-dose methotrexate (HD-MTX) toxicity is a key issue in the individualization of treatment in childhood acute lymphoblastic leukemia (ALL). Our aim was to evaluate the influence of MTX pathway polymorphisms on HD-MTX treatment outcome in children with ALL. In total, 167 children with ALL were genotyped for methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G > A, methylenetetrahydrofolate reductase (MTHFR) 677C > T and 1298A > C and thymidylate synthase (TYMS) 2R > 3R polymorphisms. The MTHFD1 1958A allele significantly reduced the odds of hepatotoxicity (adjusted p = 0.009), while the TYMS 3R allele significantly reduced the odds of leukocytopenia and thrombocytopenia (adjusted p = 0.005 and adjusted p = 0.002, respectively). MTHFR polymorphisms did not influence HD-MTX-related toxicity, but a significant effect of MTHFR 677C > T-TYMS 2R > 3R and MTHFD1 1958G > A-MTHFR 677C > T interactions on HD-MTX-related toxicity was observed. None of the investigated polymorphisms influenced survival. Our study suggests an important role of polymorphisms and gene-gene interactions within the folate pathway in HD-MTX-related toxicity in childhood ALL.

MTHFR Gene Polymorphisms and Methotrexate Toxicity in Adult Patients with Hematological Malignancies: A Meta-Analysis

“…Our meta-analysis found no significant association between MTHFR A1298C polymorphism and hepatic and hematological toxicity, which is in agreement with results reported in previous studies [19,20]. The combined analysis suggested that there may be a possibly protective effect of MTHFR A1298C mutation for grade 1-4 mucositis and gastrointestinal toxicity.…”

Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma

“…MTHFD1 is essential for the generation of methylene-THF required for thymidylate synthesis and MTHFD1 rs2236225 (Arg653Gln) was shown to reduce the enzyme activity33, leading to increased levels of methylene-THF and reducing cytotoxic effects of PMX 23,34. To our knowledge, no previous studies investigated the role of MTHFD1 SNPs in treatment with PMX.…”

“…Genotyping of MTRR rs1801394 (Ile22Met), MTR rs1805087 (Asp919Gly), SLC19A1 rs1051266 (Arg27Cys), SLCO1B1 rs11045879 (intronic), rs4149056 (Val174Ala) and rs2900478 (intronic), ABCC2 rs717620 (5’ untranslated region (UTR) -24C>T), rs2273697 (Val417Ile) and rs2804402 (5’ UTR -1019A>G), ABCC4 rs2274407 (Lys304Asn), and ABCG2 rs2231142 (Gln141Lys) and rs2231137 (Val12Met) polymorphisms was carried out using a fluorescence-based competitive allele-specific (KASPar) assay according to the manufacturer’s instructions (KBiosciences, Herts, UK). Determination of promoter TYMS rs34743033 (5’ UTR 2R>3R) polymorphism23 and ABCB1 rs2032582 (Ala893Ser/Thr) polymorphism was carried out using PCR amplification followed by the analysis of PCR fragments on agarose gel as previously described 24…”

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

“…MTHFR polymorphisms were also interactions with other polymorphisms, such as RFC, 19-bp deletion, and TS. Erčulj et al [57] found that MTHFD1 A1958G and MTHFR C677T polymorphisms had an antagonistic effect interaction on hepatotoxicity [SF=0.02, 95 %CI=0.00-0.58, P=0.022]. Other authors were also analyzed by the gene-gene interactions between MTHFR and other polymorphisms which have referred in the former sections [53,57,58].…”