The Importance of Polymorphisms in Folate-Metabolizing Genes and the Risk of Non-Hodgkin Lymphoma

Martyn Smith, Ph.D.
University of California, Berkeley
P30ES01896

Background: Folate is an important nutrient required for such diverse actions as the proper closing of the neural tube during mammalian development, for DNA synthesis, and for the prevention of cancer. Deviations in the metabolism of folate due to genetic variations have been suggested as possible factors in the susceptibility to various cancers including lymphoma. To test this hypothesis, this NIEHS-supported research team investigated genetic polymorphisms in the folate metabolic pathway using DNA from a population-based case-control epidemiologic study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco metropolitan area between 1988 and 1995. Polymorphisms in the genes coding for enzymes involved in folate metabolism were examined including thymidylate synthase, 5.10-methylenetetrahydrofolate reductase, serine hydroxymethyltransferase, methionine synthase, and reduced folate carrier, making this study the largest and most inclusive to date related to NHL risk.

Advance: Three polymorphisms in the thymidylate synthase gene were found to be inversely associated with NHL risk. Two polymorphisms in the methylenetetrahydrofolate reductase genes were found to be associated with an increased risk for NHL and follicular lymphoma. Taken together, these associations suggest that folate metabolism may play an important role in the development of specific types of NHL.

Implications: These findings suggest that both DNA synthesis and repair and methylation processes could be important in the pathogenesis of specific forms of non-Hodgkin lymphoma. Further studies are underway to investigate further the role of thymidylate synthase in lymphoma risk. These findings are also consistent with earlier reports emphasizing the need for more and larger studies to confirm these results.

Citation: Skibola CF, Forrest MS, Coppede F, Agana L, Hubbard A, Smith MT, Bracci PM, Holly EA. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood. 2004 Oct 1;104(7):2155-62. Epub 2004 Jun 15.