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

Abstract

Genetic alteration is considered a probable cause of malignant lymphoma. Folate and methionine metabolism play essential roles in DNA synthesis and DNA methylation, and their metabolic pathways might thus affect disease susceptibility. In the present study, 2 polymorphisms were evaluated for a folate metabolic enzyme, methylenetetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms, MTHFR677 C3T and MTHFR1298 A3C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5,10-methylenetetrahydrofolate and results in a reduced incidence of DNA double-strand breakage. The MS2756 A3G polymorphism also reduces the enzyme activity and results in the hypomethylation of DNA. To evaluate the association between malignant lymphoma susceptibility and these polymorphisms, hospitalbased case-control study was conducted in Aichi Cancer Center. Ninety-eight patients with histologically confirmed lymphoma and 243 control subjects without cancer were evaluated. Unconditional logistic regression analyses revealed a higher susceptibility with the MTHFR677 CC and the MTHFR1298 AA genotypes (odds ratio, 2.26; 95% confidence interval, 1.26-4.02) when those harboring at least one variant allele in either polymorphism of MTHFR were defined as the reference. For the MS polymorphism, the MS2756 GG genotype also showed a higher susceptibility (odds ratio, 3.83; 95% CI, 1.21-12.1) than those with MS2756 AA or AG types. The significance was not altered when these 3 polymorphisms were evaluated in combination, and the results suggest that folate and methionine metabolism play important roles in the occurrence of malignant lymphomas. IntroductionBiologic mechanisms underlying the genesis of lymphoid malignancies remain to be clarified in detail. However, accumulated evidence suggests that certain genetic events during cell differentiation, such as chromosomal translocation, 1,2 play an important role. Methylation status of various oncogenes or tumor suppressor genes may induce the selective growth transformation of cells or its inhibition. 3 Regardless, a single genetic event is insufficient to explain carcinogenesis of lymphoid tissue, as supported by the transgenic mouse experiment. 4 Folic acid is an important nutrient required for DNA synthesis, and the related methionine metabolic pathway is necessary for DNA methylation (Figure 1). An antifolic acid agent, methotrexate, has proven to be an effective chemotherapeutic drug for lymphoid malignancies, giving insight into the association between folate metabolism and the carcinogenesis of these malignancies.Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate (methylene THF) to 5-methyltetrahydrofolate (5-methyl THF), 5 the predominant circulatory form of folate and carbon donor for the remethylation of homocysteine to methionine (Figure 1). The MTHFR gene, which is located on chromosome 1p36, 6 is reported to have 2 polymorphisms involving nucleotides 677 (C3T;...

Lack of association between genetic polymorphisms in three folate-related enzyme genes and male infertility in the Chinese population

“…Methionine synthase (MS) catalyzes the transfer of a methyl group from 5-methyl THF to homocysteine, which produces methionine and THF [13]. A common polymorphism at position 2756 within the MTR gene (A2756G, rs1805087) results in a transition from adenine to guanine that was thought to be associated with enzyme activity [14]. MTRR catalyzes the reductive methylation of MS using S-adenosylmethionine providing the methyl group, and may also participate in DNA methylation [15].…”

Role of polymorphism of methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G and breast cancer risk

“…Primers were for each polymorphism as follows. The primers of MTR A2756G were forward 5'-TGTTCCAGACAGTTA-GATGAAAATC-3' and reverse 5'-GATCCAAAGC-CTTTTACACTCCTC-3' [16]. The cycling conditions were 94°C, 30 s; 57°C, 30 s; 72°C, 60 s (35 cycle).…”

Methionine synthase A2756G polymorphism and cancer risk: a meta-analysis

“…2 A common polymorphism in methionine synthase (MTR) gene (2756A-G, rs1805087) was initially thought to be associated with lower enzyme activity than MTR 2756AA genotype, causing homocysteine elevation and DNA hypomethylation. 3 However, in subsequent investigations, some studies suggested a modest inverse association between 2756GG polymorphism and homocysteine levels, indicating an increased enzymatic activity of the variant genotype. 4 Moreover, Paz et al 5 found that individuals who carried 2756GG showed a lower frequency of CpG island hypermethylation in tumor suppressor genes.…”