Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma

Genetic alteration is considered a probable cause of malignant lymphoma. Fo late and methionine metabolism play essential roles in DNA synthesis and DN A methylation, and their metabolic pathways might thus affect disease susce ptibility. In the present study, 2 polymorphisms were evaluated for a folat e metabolic enzyme, methylenetetrahydrofolate reductase (MTHFR), and one wa s evaluated for methionine synthase (MS). The 2 polymorphisms, MTHFR677 C-- >T and MTHFR1298 A-->C, are reported to reduce the enzyme activity, which c auses intracellular accumulation of 5,10-methylenetetrahydrofolate and resu lts in a reduced incidence of DNA double-strand breakage. The MS2756 A-->G polymorphism also reduces the enzyme activity and results in the hypomethyl ation of DNA. To evaluate the association between malignant lymphoma suscep tibility and these polymorphisms, hospital-based case-control study was con ducted in Aichi Cancer Center. Ninety-eight patients with histologically co nfirmed lymphoma and 243 control subjects without cancer were evaluated. Un conditional logistic regression analyses revealed a higher susceptibility w ith the MTHFR677 CC and the MTHFR1298 AA genotypes (odds ratio, 2.26; 95% c onfidence interval, 1.26-4.02) when those harboring at least one variant al lele in either polymorphism of MTHFR were defined as the reference. For the MS polymorphism, the MS2756 GG genotype also showed a higher susceptibilit y (odds ratio, 3.83; 95% CI, 1.21-12.1) than those with MS2756 AA or AG typ es. The significance was not altered when these 3 polymorphisms were evalua ted in combination, and the results suggest that folate and methionine meta bolism play important roles in the occurrence of malignant lymphomas. Furth er studies to confirm the association and detailed biologic mechanisms are now required. (Blood. 2001;97:3205-3209) (C) 2001 by The American Society o f Hematology.