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

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), 6 bp 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 28 bp 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.