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Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 [C. M. U., J. B., J. D. P.]; Department of Epidemiology, University of Washington, Seattle, Washington 98195 [C. M. U., J. D. P.]; University of Minnesota, Minneapolis, Minnesota 55414 [L. F.]; and University of South Carolina, Columbia, South Carolina 29208 [R. B.]
Thymidylate synthase (TS) is a key enzyme in folate metabolism and the primary target of 5-fluorouracil. A repeat polymorphism in the TS promoter enhancer region (2rpt versus 3rpt of 28 bp) is associated with decreased expression, and a 6-bp deletion in the 3'untranslated region may affect RNA stability. We investigated the role of TS polymorphisms in a case control study of adenomatous polyps (510 cases and 604 polyp-free controls). Multivariate-adjusted odds ratios (ORs; 95% confidence interval) for TSER 2rpt/3rpt and 2rpt/2rpt compared with 3rpt/3rpt were 0.8 (0.6–1.2) and 0.9 (0.6–1.3), respectively. We observed a significant gene-nutrient interaction between the TSER polymorphism and folate intake: among 3rpt/3rpt individuals (greater expression), folate intake > 440 µg/day (highest tertile) versus 
440 µg/day was associated with a 2-fold decreased risk [ORs 1.0 (reference group) versus 0.5 (0.3–0.9)]. However, among 2rpt/2rpt individuals, high folate intake was associated with a 1.5-fold increased risk [ORs 0.6 (0.4–0.9) versus 0.9 (0.5–1.5; P for interaction = 0.03)]. Vitamin B12 showed a similar trend (P = 0.08). No clear pattern was seen with the TS 1494del6 polymorphism. These findings raise questions regarding the molecular pathways linking folate metabolism and colorectal carcinogenesis, including whether high folate is beneficial in the presence of all metabolic genotypes.
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