Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes.
Genetic instability, including chromosomal imbalance, is important in the pathogenesis of lymphoproliferative disorders such as non-Hodgkin lymphoma (NHL). DNA synthesis and methylation, which are closely linked to folate metabolism and transport, may be affected by polymorphisms in genes involved in these pathways. Folate metabolism polymorphisms have been linked to acute lymphoblastic leukemia and colorectal cancer. To evaluate whether genetic variation in folate metabolism and transport may have a role in determining the risk of developing NHL, we analyzed several polymorphisms using DNA obtained as part of a large U.K. population-based case-control study of lymphoma. Polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C >T and 1298 A >C, methionine synthase (MTR) 2756 A>G, serine hydroxymethyltransferase (SHMT1) 1420 C >T, thymidylate synthase (TYMS) 1494del6 and 28-bp repeat, and reduced folate carrier (RFC) 80 G >A. Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant. Marginal increased risks were also observed for diffuse large B cell lymphoma with the TYMS homozygous 6 bp deletion (OR, 1.61; 95% CI, 0.99-2.60) and for follicular lymphoma with RFC 80AA (OR, 1.44; 95% CI, 0.94-2.22) and TYMS 28-bp repeat 2R/3R (OR, 1.45; 95% CI, 0.96-2.2). We observed no association between NHL and haplotypes for MTHFR or TYMS. These findings are somewhat inconsistent with those of others, but may reflect differences in circulating folate levels between study populations. Thus, further investigations are warranted in larger series with dietary information to determine the roles that genetics and folic acid status play in the etiology of lymphoma.
Lightfoot
Tracy J
TJ
Epidemiology and Genetics Unit, Department of Health Sciences, University of York, Area 3, Seebohm Rowntree Building YO10 5DD, York, United Kingdom. tracy.lightfoot@egu.york.ac.uk
Skibola
Christine F
CF
Willett
Eleanor V
EV
Skibola
Danica R
DR
Allan
James M
JM
Coppede
Fabio
F
Adamson
Peter J
PJ
Morgan
Gareth J
GJ
Roman
Eve
E
Smith
Martyn T
MT
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D016022:Case-Control Studies; D004247:DNA / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D014644:Genetic Variation; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008228:Lymphoma, Non-Hodgkin / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000235:genetics
D004247:DNA; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase; D012696:Glycine Hydroxymethyltransferase