title: Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma.
abstract: Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect susceptibility to various cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using DNA from a population-based case-control study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco Bay Area between 1988 and 1995. The polymorphisms examined and haplotypes generated included thymidylate synthase (TYMS 28-bp triple repeat [3R]-->double repeat [2R], 1494del6, IVS6 -68C>T, 1122A>G, and 1053C>T); 5,10-methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C); serine hydroxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC G80A); and methionine synthase (MTR A2756G), making the present study the largest and most comprehensive to date to evaluate associations between genetic polymorphisms in folatemetabolizing genes and NHL risk. The TYMS 6 base pair (bp)(-)6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively. We did not observe any significant differences in genotype frequencies of the SHMT1 and RFC polymorphisms between the cases and controls. The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL.
authors.affiliation: Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA. chrisfs@berkeley.edu
authors.forename: Christine F
authors.initials: CF
authors.lastname: Skibola
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Forrest
authors.forename: Fabio
authors.initials: F
authors.lastname: Coppedé
authors.forename: Luz
authors.initials: L
authors.lastname: Agana
authors.forename: Alan
authors.initials: A
authors.lastname: Hubbard
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holly
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004247:DNA / Q000378:metabolism; D005091:Exons; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005838:Genotype; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D008297:Male; D045102:Methylenetetrahydrofolate Dehydrogenase (NAD+) / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012306:Risk; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D004247:DNA; D005492:Folic Acid; D045102:Methylenetetrahydrofolate Dehydrogenase (NAD+); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase; D012696:Glycine Hydroxymethyltransferase