{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:24:18Z","timestamp":1774592658374,"version":"3.50.1"},"reference-count":40,"publisher":"American Society of Hematology","issue":"10","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,5,15]]},"abstract":"<jats:p>We previously reported that 2 polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic leukemia (ALL). In the present study, we have examined whether polymorphisms in other folate-metabolizing genes play a role in ALL susceptibility. Polymorphisms in methionine synthase (MS A2756G), cytosolic serine hydroxymethyltransferase (SHMT1 C1420T), and a double (2R2R) or triple (3R3R) 28-bp tandem repeat in the promoter region of thymidylate synthase (TS) were studied and found to modulate ALL risk. In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR]\u2009=\u20090.48; 95% confidence interval [CI], 0.25-0.91), whereas the 1420TT genotype conferred a 3.3-fold reduction in risk (OR\u2009=\u20090.31; 95% CI, 0.10-0.90). Similarly, TS 2R3R individuals exhibited a 2.8-fold reduction in ALL risk (OR\u2009=\u20090.36; 95% CI: 0.16-0.83), while the TS 3R3R genotype conferred an even greater level of protection (OR\u2009=\u20090.25; 95% CI, 0.08-0.78). However, no significant associations were evident for the MS 2756AG polymorphism (OR\u2009=\u20090.79; 95% CI, 0.38-1.7). In addition, potential interactions between theSHMT1 and TS or MS genes were observed. TS 3R3R individuals who were SHMT1 1420CT\/TT had a 13.9-fold decreased ALL risk (OR\u2009=\u20090.072; 95% CI, 0.0067-0.77). Further, MS 2756AG individuals who were SHMT1 1420CT\/TT had a 5.6-fold reduction in ALL risk (OR\u2009=\u20090.18; 95% CI, 0.05-0.63). This study suggests an important role for uracil misincorporation and resultant chromosomal damage in the pathogenesis of ALL, and that genetic interactions involving low penetrance polymorphisms in folate-metabolizing genes may increase ALL risk.<\/jats:p>","DOI":"10.1182\/blood.v99.10.3786","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T21:48:18Z","timestamp":1033508898000},"page":"3786-3791","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":189,"title":["Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia"],"prefix":"10.1182","volume":"99","author":[{"given":"Christine F.","family":"Skibola","sequence":"first","affiliation":[{"name":"From the NFCR Center for Genomics and Nutrition, School of Public Health, and the Department of Nutritional Sciences, University of California, Berkeley, CA; the Leukaemia Research 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Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barry","family":"Shane","sequence":"additional","affiliation":[{"name":"From the NFCR Center for Genomics and Nutrition, School of Public Health, and the Department of Nutritional Sciences, University of California, Berkeley, CA; the Leukaemia Research Fund Centre for Clinical Epidemiology, Leeds, and the Department of Haematology, University of Leeds, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abby C.","family":"Roberts","sequence":"additional","affiliation":[{"name":"From the NFCR Center for Genomics and Nutrition, School of Public Health, and the Department of Nutritional Sciences, University of California, Berkeley, CA; the Leukaemia Research Fund Centre for Clinical Epidemiology, Leeds, and the Department of Haematology, University of Leeds, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham 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A."},{"key":"2020021216301855300_B3","first-page":"977","article-title":"Expression of fragile site on the human X chromosome in somatic cell hybrids between human fragile X cells and thymidylate synthase-negative mouse mutant cells.","volume":"76","author":"Hori","year":"1985","journal-title":"Jpn J Cancer Res."},{"key":"2020021216301855300_B4","first-page":"703","article-title":"Chromosome breakage induced by thymidylate stress in thymidylate synthase-negative mutants of mouse FM3A cells.","volume":"44","author":"Hori","year":"1984","journal-title":"Cancer Res."},{"key":"2020021216301855300_B5","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1093\/nar\/15.3.1259","article-title":"Role in translation of a triple tandemly repeated sequence in the 5\u2032-untranslated region of human thymidylate synthase mRNA.","volume":"15","author":"Kaneda","year":"1987","journal-title":"Nucleic Acids Res."},{"key":"2020021216301855300_B6","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1247\/csf.20.191","article-title":"Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5\u2032-terminal regulatory region of the human gene for thymidylate synthase.","volume":"20","author":"Horie","year":"1995","journal-title":"Cell Struct Funct."},{"key":"2020021216301855300_B7","first-page":"3249","article-title":"Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers.","volume":"19","author":"Kawakami","year":"1999","journal-title":"Anticancer Res."},{"key":"2020021216301855300_B8","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1146\/annurev.nu.05.070185.000555","article-title":"Vitamin B12-folate interrelationships.","volume":"5","author":"Shane","year":"1985","journal-title":"Annu Rev 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uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage.","volume":"94","author":"Blount","year":"1997","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021216301855300_B27","doi-asserted-by":"crossref","first-page":"9883","DOI":"10.1021\/bi00156a005","article-title":"Structural basis for recognition of polyglutamyl folates by thymidylate synthase.","volume":"31","author":"Kamb","year":"1992","journal-title":"Biochemistry."},{"key":"2020021216301855300_B28","doi-asserted-by":"crossref","first-page":"18375","DOI":"10.1074\/jbc.272.29.18375","article-title":"Identification of functional elements in the promoter region of the human gene for thymidylate synthase and nuclear factors that regulate the expression of the gene.","volume":"272","author":"Horie","year":"1997","journal-title":"J Biol Chem."},{"key":"2020021216301855300_B29","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1093\/carcin\/18.2.287","article-title":"Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate\/methyl deficient rats.","volume":"18","author":"James","year":"1997","journal-title":"Carcinogenesis."},{"key":"2020021216301855300_B30","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1096\/fasebj.12.14.1491","article-title":"DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro.","volume":"12","author":"Duthie","year":"1998","journal-title":"FASEB Journal."},{"key":"2020021216301855300_B31","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1021\/bi00359a022","article-title":"DNA fragmentation and cytotoxicity from increased cellular 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retardation.","volume":"18","author":"Tommerup","year":"1981","journal-title":"J Med Genet."},{"key":"2020021216301855300_B35","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0378-1119(98)00085-7","article-title":"Molecular cloning, characterization and alternative splicing of the human cytoplasmic serine hydroxymethyltransferase gene.","volume":"210","author":"Girgis","year":"1998","journal-title":"Gene."},{"key":"2020021216301855300_B36","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1016\/S0021-9258(18)52328-0","article-title":"5-Formyltetrahydrofolate polyglutamates are slow tight binding inhibitors of serine hydroxymethyltransferase.","volume":"266","author":"Stover","year":"1991","journal-title":"J Biol Chem."},{"key":"2020021216301855300_B37","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1007\/978-1-4615-2960-6_141","article-title":"Evidence that 5-formyltetrahydropteroylglutamate has a metabolic role in one-carbon metabolism.","volume":"338","author":"Stover","year":"1993","journal-title":"Adv Exp Med Biol."},{"key":"2020021216301855300_B38","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0065-2571(84)90021-9","article-title":"Enzymes of serine metabolism in normal, developing and neoplastic rat tissues.","volume":"22","author":"Snell","year":"1984","journal-title":"Adv Enzyme Regul."},{"key":"2020021216301855300_B39","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/S0065-2571(99)00035-7","article-title":"The genetic organization and protein crystallographic structure of human serine hydroxymethyltransferase.","volume":"40","author":"Snell","year":"2000","journal-title":"Adv Enzyme Regul."},{"key":"2020021216301855300_B40","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1016\/S0140-6736(01)06959-8","article-title":"Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control 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