5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Acute Lymphoblastic Leukemia Risk: A Meta-analysis Tiago Veiga Pereira, 1 Martina Rudnicki, 2 Alexandre Costa Pereira, 3 Maria S. Pombo-de-Oliveira, 4 and Rendrik Franc ¸aFranco 5 1 Department of Biochemistry and Molecular Biology, Federal University of Sa ˜o Paulo; 2 Clinical and Toxicological Analysis Department, Faculty of Pharmaceutical Sciences, and 3 Heart Institute (Instituto do Corac ¸a ˜o),Sa ˜o Paulo University Medical School, University of Sa ˜o Paulo; 4 Division of Experimental Medicine, Instituto Nacional de Ca ˆncer, Rio de Janeiro, Rio de Janeiro, Brazil; and 5 Fleury Research Institute, Sa ˜o Paulo, Sa ˜o Paulo, Brazil Abstract There is evidence supporting a role for 5-10 methylenetetra- hydrofolate reductase (MTHFR ) gene variants in acute lymphoblastic leukemia (ALL). To provide a more robust estimateoftheeffectof MTHFR polymorphismsontheriskof ALL, we did a meta-analysis to reevaluate the association between the two most commonly studied MTHFR polymor- phisms (C677T and A1298C) and ALL risk. All case-control studies investigating an association between the C677T or A1298C polymorphisms and risk of ALL were included. We applied both fixed-effects and random-effects models to combine odds ratio (OR) and 95% confidence intervals (95% CI). Q-statistic was used to evaluate the homogeneity andbothEggerandBegg-Mazumdartestswereusedtoassess publication bias. The meta-analysis of the C677T polymor- phismandriskofchildhoodALLincluded13studieswitha totalof4,894individuals.Underafixed-effectsmodel,theTT genotypefailedtobeassociatedwithastatisticallysignificant reductionofchildhoodALLrisk(TTversusCT+CC:OR,0.88; 95% CI, 0.73-1.06; P = 0.18). However, individuals homo- zygousforthe677Talleleexhibiteda2.2-folddecreaseinrisk ofadultALL(TTversusCT+CC:OR,0.45;95%CI,0.26-0.77; P = 0.004). In both cases, no evidence of heterogeneity was observed. No association between the A1298C variant and susceptibility to both adult and childhood ALL was disclosed.Ourfindingssupporttheproposalthatthecommon geneticC677Tpolymorphisminthe MTHFR contributestothe risk of adult ALL, but not to the childhood ALL susceptibi- lity. (CancerEpidemiolBiomarkersPrev2006;15(10):1956–63) Introduction Acute lymphoblastic leukemia (ALL) is the commonest pediatric cancer in industrialized countries (1, 2). With an incidenceexpectedtoreachupto4.75casesper100.000people worldwide, ALL represents f80% of leukemia diagnoses (2). Whereas ALL accounts for 23% of cancers among children younger than 15 years, it is responsible for up to 20% of all adultleukemias,whicharecharacterizedbyaworseprognosis with a decreased long-term survival (2, 3). Although a significant improvement in both ALL diagnosis and treatment has been made over the past decades, the etiology of most cases of ALL remains unknown due to probable multifactorial mechanisms of pathogenesis (4). Recently, however, molecular epidemiologic case-control studies suggest that both adults and children harboring variant alleles of the 5,10-methylenete- trahydrofolate reductase (MTHFR ) gene might have a de- creased risk of ALL development (5). The gene coding for MTHFR enzyme is located at chromosome 1.p36.3 and composed of 2.2 kilobases with a total of 11 exons (6). Despite the fact that several MTHFR polymorphisms have been described thus far, only two polymorphisms, C677T and A1298C, have been intensively investigated. The C-to-T transition at the nucleotide position 677 in exon 4 of MTHFR generates an alanine-to-valine substitution at amino acid 222. This substitution lies at the binding site for the flavin adenine dinucleotide (7), an important cofactor for MTHFR. As a result, carriers of the MTHFR 677TT genotype possess a thermolabile enzyme of reduced activity (8), with a subsequent mild decrease in both serum and plasma folate and an increase in homocysteine levels (5, 9). The second most studied polymorphism in MTHFR is an A-to-C transversion substitution at nucleotide 1,298 (exon 7) that results in an amino acid substitution of glutamate for alanine at codon 429 (10). Once this amino acid substitution takes place at the S -adenosylmethionine regula- tory domain of the MTHFR, the A1298C polymorphism also generates an enzyme with a decreased activity (10). However, in contrast to the C677T variant, biochemical observations indicate that individuals homozygous for the 1298C allele do not seem to have higher serum homocysteine levels or any modification in folate status when compared with the wild- type genotype (9). The biological mechanism by which MTHFR variants are thought to be associated with the ALL risk modulation is related to a more efficient DNA synthesis (5). Because folate playsamajorroleinnormalhumancellgrowthandleukemias commonly arise as a result of DNA translocations, inversions, or deletions in regulatory genes of the blood cell development and homeostasis (4, 5, 11), a decreased MTHFR activity might resultinanalterationofthenormalintracellulardistributionof folate substrates (12). As a result, the folate precursors pathway would be directed for purine and pyrimidine synthesis, generating a reduced uracil misincorporation (13) with a subsequent decreased number of genetic mutations and a more stable DNA synthesis. Despite the appealing biological mechanism, results on the relation between MTHFR poly- morphisms and ALL risk are derived mainly from underpow- ered studies and yielded conflicting results. To investigate the possible effect of MTHFR variants on the ALL risk through a more robust and powered analysis, we did a meta-analysis of 13 molecular epidemiologic case-control studies that examined 1956 Cancer Epidemiol Biomarkers Prev 2006;15(10). October 2006 Received 4/24/06; revised 7/7/06; accepted 7/19/06. Grant support: Coordenac ¸a ˜o de Aperfeic ¸oamento Pessoal de Nı ´vel Superior and scholarship CNPq #308532/2003-1 (M.S. Pombo-de-Oliveira). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Tiago V. Pereira, Department of Biochemistry and Molecular Biology, Federal University of Sa ˜o Paulo, Instituto do Corac ¸a ˜o, Avenida Dr. Ene ´as de Carvalho Aguiar 44, CEP 05403-000, Sa ˜o Paulo, SP, Brazil. Phone: 55-11-3069-5068; Fax: 55-11-3069-5068. E-mail: t27026t@yahoo.com.br Copyright D 2006 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-06-0334 on April 23, 2020. © 2006 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from