Polymorphism in the Thymidylate Synthase Promoter Enhancer Region Modifies the Risk and Survival of Colorectal Cancer

Polymorphism in the Thymidylate Synthase Promoter Enhancer Region Modifies the Risk and Survival of Colorectal Cancer1

Departments of Community and Preventive Medicine [J. C., C. K., W. C.] and Microbiology [J. G. W.], Mount Sinai School of Medicine, New York, New York 10029; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital [D. J. H., M. J. S., J. M.] and Harvard Medical School, Departments of Epidemiology [D. J. H., M. J. S.] and Nutrition [M. J. S.], Harvard School of Public Health, Boston, Massachusetts; Washington Lee University, Virginia [R. M.]; and Jean Mayer United States Department of Agriculture Human Nutrition Center on Aging at Tufts University, Boston, Massachusetts [J. S.]

Abstract

Thymidylate synthase (TS) converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. It is also the target for 5-flurorouracil, the most common chemotherapy agent for treatment of colorectal cancer (CRC). We designed a nested case-control study within the prospective Physicians’ Health Study to investigate whether TS polymorphisms independently predict risk of CRC and simultaneously the overall survival after the disease in the same population. We also investigated influences of this polymorphism on plasma folate and homocysteine levels. The study consists of 270 incident CRC and 454 control subjects. Risk of CRC was estimated by use of conditional multiple logistic regression analysis. Survival was analyzed by Cox proportional hazards regression analysis. Compared with the TS 3R/3R genotype, the multivariate-adjusted risk ratio was 0.86 (0.59–1.25) for the 2R/3R genotype and 0.59 (0.36–0.98) for the 2R/2R genotype with P for trend of 0.03. The TS 2R/2R genotype was also associated with better survival, although the results were not significant. Compared with those with either the 3R/3R or 2R/3R genotypes, the age-adjusted hazard ratio for the 2R/2R genotype was 0.57 (0.30–1.07). Individuals with the 2R/2R genotype had significantly lower plasma folate levels than those with the 3R/3R genotype, whereas their plasma homocysteine levels were unaffected by the TS promoter polymorphism. The deletion polymorphism at the TS 3′-untranslated region did not influence the CRC risk and survival, nor did it modify the plasma folate and total homocysteine levels. Given that individuals with high plasma folate had a better survival outcome with a hazard ratio of 0.68 (0.45–1.03) compared with those with low plasma folate, we conclude that the TS promoter polymorphism may modify both the risk and the survival of CRC; however, these effects do not appear to be mediated through its modulation of biological folate levels.

Footnotes

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↵1 This work was supported by research Grants CA 42182 and CA 87969 from NIH. J. C. was supported by a career development award CA 81750 from National Cancer Institute. J. S. was supported by the United States Department of Agriculture under cooperative agreement No.58-1950-9-001.
↵2 To whom requests for reprints should be addressed, at Department of Community and Preventive Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: (212) 241-7519; Fax: (212) 360-6965; E-mail: jia.chen{at}mssm.edu
↵3 The abbreviations used are: CRC, colorectal cancer; TS, thymidylate synthase; 5-FU, 5-flurorouracil; tHcy, total homocysteine; MTHFR, methylenetetrahydrofolate reductase; HR, hazard ratio; CI, confidence interval; UTR, untranslated region.
- Accepted June 11, 1903.
- Received February 17, 1903.
- Revision received May 16, 1903.