Effects of thymidylate synthase polymorphisms on toxicities associated with high-dose methotrexate in childhood acute lymphoblastic leukemia.

Abstract

High-dose methotrexate (HD- MTX) is the cornerstone of chemotherapy for acute lymphoblastic leukemia (ALL), and one of its target enzymes is Thymidylate Synthase (TYMS). We hypothesized that genetic polymorphisms of TYMS gene would be associated with MTX toxicity in ALL children. 64 children with ALL were included in this study. Genotyping analysis was conducted on three common polymorphisms: tandem repeats in the promoter-enhancer region (VNTR), 6bp ins/del (1494del6) in the 5'UTR, and rs2790 A > G in the 3'-untranslated region (3'-UTR). The association between genetic polymorphisms and MTX toxicity was studied. Genetic polymorphism of TYMS was associated with hematological toxicities but not with non-hematological adverse events. A significant association between TYMS 1494del6 genotypes and incidence of neutropenia (ANC < 1700 mm3), infection and leukopenia was observed. Carriers of the dominant allele (Del) were 6 times more likely to develop neutropenia compared to minor genotype carriers (OR (95% CI) 6 (1.2-31.1); p = 0.04), and 4.2 times less likely to have infection, as compared to Ins/Ins carriers (OR  4.2, 95% CI (1.1-16); p = 0.04). Carriers of Del allele were 9.2 times more likely to develop grade 3 and 4 leukopenia, p = 0.02, 95% CI (1.1-75.6). Significant association was found between 28bp VNTR and thrombocytopenia; (OR  3.3, 95% CI (1.1-10), p = 0.04). No significant association was found between TYMS rs2790 A > G genetic polymorphisms and MTX hematologic toxicities. Genetic polymorphism of TYMS1494del6 may modulate susceptibility to MTX toxicity.