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

• Published in: Cancer epidemiology, biomarkers & prevention Vol. 13; no. 5; pp. 787 - 794
• Main Authors: GEMMATI, Donato, ONGARO, Alessia, CARUSO, Angelo, PASELLO, Michela, PELLATI, Agnese, DE MATTEI, Monica, SCAPOLI, Gian L, DELLA PORTA, Matteo, TOGNAZZO, Silvia, SERINO, Maria L, DI BONA, Eros, RODEGHIERO, Francesco, GILLI, Giuseppe, REVERBERI, Roberto
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-05-2004
• Subjects: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - genetics; 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - metabolism; Adolescent; Adult; Age Distribution; Aged; Base Sequence; Biological and medical sciences; Case-Control Studies; Cohort Studies; Confidence Intervals; Female; Ferredoxin-NADP Reductase - genetics; Ferredoxin-NADP Reductase - metabolism; Genetic Predisposition to Disease; Genotype; Hematologic and hematopoietic diseases; Humans; Incidence; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Non-Hodgkin - epidemiology; Lymphoma, Non-Hodgkin - genetics; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Odds Ratio; Polymerase Chain Reaction; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma - epidemiology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Probability; Prognosis; Risk Assessment; Sex Distribution; Italy; Europe; O-Acetylhomoserine (thiol)-lyase; Methylenetetrahydrofolate reductase (NADPH); Genetic variability; Lyases; Metabolic pathway; Case control study; Epidemiology; Folate; Cancerology; [Methionine synthase]-cobalamin methyltransferase (cob(II)alamin reducing); Lymphoproliferative syndrome; Genetics; Adult; Acute lymphocytic leukemia; Public health; Human; Enzyme; Transferases; Acute; Genotype; Malignant hemopathy; Non Hodgkin lymphoma; Methyltransferases; Risk factor; Oxidoreductases; Methylation; Carbon-oxygen lyases; Polymorphism
• ISSN: 1055-9965; 1538-7755
• DOI: 10.1158/1055-9965.787.13.5

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.