This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, J. Articles by Ma, J. Search for Related Content PubMed PubMed Citation Articles by Chen, J. Articles by Ma, J.

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.]

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.

This article has been cited by other articles:

				A. Y. Jung, E. M. Poole, J. Bigler, J. Whitton, J. D. Potter, and C. M. Ulrich DNA Methyltransferase and Alcohol Dehydrogenase: Gene-Nutrient Interactions in Relation to Risk of Colorectal Polyps Cancer Epidemiol. Biomarkers Prev., February 1, 2008; 17(2): 330 - 338. [Abstract] [Full Text] [PDF]

				R. Sharma, J. M. Hoskins, L. P. Rivory, M. Zucknick, R. London, C. Liddle, and S. J. Clarke Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphisms and Toxicity to Capecitabine in Advanced Colorectal Cancer Patients Clin. Cancer Res., February 1, 2008; 14(3): 817 - 825. [Abstract] [Full Text] [PDF]

				M. Wrensch, A. McMillan, J. Wiencke, J. Wiemels, K. Kelsey, J. Patoka, H. Jones, V. Carlton, R. Miike, J. Sison, et al. Nonsynonymous Coding Single-Nucleotide Polymorphisms Spanning the Genome in Relation to Glioblastoma Survival and Age at Diagnosis Clin. Cancer Res., January 1, 2007; 13(1): 197 - 205. [Abstract] [Full Text] [PDF]

				R. A. Hubner, K. R. Muir, J.-F. Liu, G. S. Sellick, R. F.A. Logan, M. Grainge, N. Armitage, I. Chau, R. S. Houlston, and The United Kingdom Colorectal Adenoma Prevention C Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence. Cancer Epidemiol. Biomarkers Prev., September 1, 2006; 15(9): 1607 - 1613. [Abstract] [Full Text] [PDF]

				E. Dotor, M. Cuatrecases, M. Martinez-Iniesta, M. Navarro, F. Vilardell, E. Guino, L. Pareja, A. Figueras, D. G. Mollevi, T. Serrano, et al. Tumor Thymidylate Synthase 1494del6 Genotype As a Prognostic Factor in Colorectal Cancer Patients Receiving Fluorouracil-Based Adjuvant Treatment J. Clin. Oncol., April 1, 2006; 24(10): 1603 - 1611. [Abstract] [Full Text] [PDF]

				C. M. Ulrich, K. Curtin, J. D. Potter, J. Bigler, B. Caan, and M. L. Slattery Polymorphisms in the Reduced Folate Carrier, Thymidylate Synthase, or Methionine Synthase and Risk of Colon Cancer Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2509 - 2516. [Abstract] [Full Text] [PDF]

				C. M. Ulrich Nutrigenetics in Cancer Research--Folate Metabolism and Colorectal Cancer J. Nutr., November 1, 2005; 135(11): 2698 - 2702. [Abstract] [Full Text] [PDF]

				Z. Zhang, Y. Xu, J. Zhou, X. Wang, L. Wang, X. Hu, J. Guo, Q. Wei, and H. Shen Polymorphisms of thymidylate synthase in the 5'- and 3'-untranslated regions associated with risk of gastric cancer in South China: a case-control analysis Carcinogenesis, October 1, 2005; 26(10): 1764 - 1769. [Abstract] [Full Text] [PDF]

				W. Tan, X. Miao, L. Wang, C. Yu, P. Xiong, G. Liang, T. Sun, Y. Zhou, X. Zhang, H. Li, et al. Significant increase in risk of gastroesophageal cancer is associated with interaction between promoter polymorphisms in thymidylate synthase and serum folate status Carcinogenesis, August 1, 2005; 26(8): 1430 - 1435. [Abstract] [Full Text] [PDF]

				E. K. Wei, E. Giovannucci, J. Selhub, C. S. Fuchs, S. E. Hankinson, and J. Ma Plasma Vitamin B6 and the Risk of Colorectal Cancer and Adenoma in Women J Natl Cancer Inst, May 4, 2005; 97(9): 684 - 692. [Abstract] [Full Text] [PDF]

				S. Popat, R. Wort, and R. S. Houlston Relationship Between Thymidylate Synthase (TS) Genotype and TS Expression: A Tissue Microarray Analysis of Colorectal Cancers International Journal of Surgical Pathology, April 1, 2005; 13(2): 127 - 133. [Abstract] [PDF]

				Q. Shi, Z. Zhang, A. S. Neumann, G. Li, M. R. Spitz, and Q. Wei Case-control analysis of thymidylate synthase polymorphisms and risk of lung cancer Carcinogenesis, March 1, 2005; 26(3): 649 - 656. [Abstract] [Full Text] [PDF]

				J. Chen, C. Kyte, W. Chan, J. G. Wetmur, C. S. Fuchs, and E. Giovannucci Polymorphism in the Thymidylate Synthase Promoter Enhancer Region and Risk of Colorectal Adenomas Cancer Epidemiol. Biomarkers Prev., December 1, 2004; 13(12): 2247 - 2250. [Abstract] [Full Text] [PDF]

				Z. Zhang, Q. Shi, E. M. Sturgis, M. R. Spitz, W. K. Hong, and Q. Wei Thymidylate Synthase 5'- and 3'-Untranslated Region Polymorphisms Associated with Risk and Progression of Squamous Cell Carcinoma of the Head and Neck Clin. Cancer Res., December 1, 2004; 10(23): 7903 - 7910. [Abstract] [Full Text] [PDF]

				Z. Kemp, C. Thirlwell, O. Sieber, A. Silver, and I. Tomlinson An update on the genetics of colorectal cancer Hum. Mol. Genet., October 1, 2004; 13(suppl_2): R177 - R185. [Abstract] [Full Text] [PDF]

				C. F. Skibola, M. S. Forrest, F. Coppede, L. Agana, A. Hubbard, M. T. Smith, P. M. Bracci, and E. A. Holly Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma Blood, October 1, 2004; 104(7): 2155 - 2162. [Abstract] [Full Text] [PDF]