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Common Gene Polymorphisms in the Metabolic Folate and Methylation Pathway and the Risk of Acute Lymphoblastic Leukemia and non-Hodgkin's Lymphoma in Adults

¹ Department of Biomedical Sciences and Advanced Therapies, Center Study for Hemostasis and Thrombosis and Unit of Hematology, and ² Department of Morphology and Embryology, Unit of Histology, University of Ferrara, Ferrara, Italy; ³ Department of Hematology, San Bortolo Hospital, Vicenza, Italy; and ⁴ Department of Health Physics and ⁵ Transfusion Center, Sant' Anna Hospital, Ferrara, Italy

Requests for reprints: Donato Gemmati, Department of Biomedical Sciences and Advanced Therapies, Center Study for Hemostasis and Thrombosis, University of Ferrara, C.so Giovecca 203, I-44100 Ferrara, Italy. Phone: 39-0532-237-291; Fax: 39-0532-209-010. E-mail: d.gemmati{at}unife.it

Folate and methionine metabolism is involved in DNA synthesis and methylation processes. Polymorphisms in the genes of folate metabolism enzymes have been associated with some forms of cancer. In a case-control study, we evaluated whether four common polymorphisms in methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A2756G), and methionine synthase reductase (MTRR A66G) genes may have a role in altering susceptibility to adult acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). We analyzed DNA of 120 adult ALL, 200 NHL, and 257 healthy control subjects. Individual carrying the MTHFR 677TT genotype showed a 3.6-fold decreased ALL risk [odds ratio (OR) 0.28, 95% confidence interval (95% CI) 0.12–0.72] than wild-types. Similarly, MS 2756GG individuals showed a 5.0-fold decreased ALL risk (OR 0.20, 95% CI 0.02–1.45) than wild-types. In combined results, subjects with the MTHFR 677CT/TT and MS 2756AG/GG genotypes revealed a 3.6-fold ALL risk reduction (OR 0.28, 95% CI 0.14–0.58) and those with the MTHFR 677TT and MTRR 66AG genotypes revealed a 4.2-fold ALL risk reduction (OR 0.24, 95% CI 0.06–0.81). Finally, those with the MS 2756AG/GG and MTRR 66AG/GG genotypes revealed a 2.2-fold ALL risk reduction (OR 0.45, 95% CI 0.10–0.85). Single analysis for NHL did not show any significant difference for all the polymorphisms investigated, but in the low-grade NHL subgroup, we found a 2.0-fold risk reduction for the MTRR 66GG homozygous genotype (OR 0.50, 95% CI 0.25–0.99), which was higher (OR 0.37, 95% CI 0.14–0.85) when analyzed in combination with MS 2756AA genotype. These data are in accordance with the hypothesis that polymorphisms in the genes for folate and methionine metabolism might play a greater role in the occurrence of ALL than NHL by influencing DNA synthesis and/or DNA methylation.

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