Abstract
High levels of thymidylate synthase (TS) expression have been associated with poor survival of colorectal cancer (CRC) patients to 5-fluorouracil (5-FU)-based chemotherapy. Recent evidence suggests that a polymorphism within the enhancer region of the TS gene promoter can influence TS expression, with the triple repeat homozygote (3R/3R) being associated with significantly higher tumour TS levels than either the double repeat homozygote (2R/2R) or heterozygotes (2R/3R). In the present study we investigated whether TS genotype was associated with the degree of survival benefit from chemotherapy in 221 Dukes’ C stage CRC patients. Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30–1.25, P = 0.18), whereas those with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52–0.82, P = 0.005). These results demonstrate that a polymorphism within the TS gene, probably through its effect on TS expression levels, can influence the survival benefit obtained by CRC patients from 5-FU-based chemotherapy. © 2001 Cancer Research Campaign http://www.bjcancer.com
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References
Ahnen DJ, Feigl P, Quan G, Fenoglio-Preiser C, Lovato LC and Bunn PA et al (1998) Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study. Cancer Res 58: 1149–1158
Anonymous (1999) Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer: International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 17: 1349–1355
Beck A, Etienne MC, Cheradame S, Fischel JL, Formento P and Renee N et al (1994) A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumor sensitivity to 5-fluorouracil. Eur J Cancer 30: 1517–1522
Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N and Iacopetta B (2000) Evidence for tumour site and gender specific survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 355: 1745–1750
Horie N, Hideo A, Oguro K, Hojo H and Takeishi K (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Structure Function 20: 191–197
Johnston PG, Drake JC, Trepel J and Allegra CJ (1992) Immunological quantitation of thymidylate synthase using the monoclonal antibody TS 106 in 5-fluorouracil-sensitive and resistant human cancer cell lines. Cancer Res 52: 4306–4312
Johnston PG, Fisher ER, Rockette HE, Fisher B, Womark N and Drake JC et al (1994) The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12: 2640–2647
Kawakami K, Omura K, Kanehira E and Watanabe Y (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19: 3249–3252
Leichman CG, Lenz HJ, Leichman L, Danenberg K, Baranda J and Groshen S et al (1997) Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol 15: 3223–3229
Lenz HJ, Leichman CG, Daneberg KD, Danenberg PC, Groshen S and Cohen H et al (1996) Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol 14: 176–182
Mamounas E, Wieand S, Wolmark N, Bear HD, Atkins JN and Song K et al (1999) Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 17: 1349–1355
Marsh S, Collie-Duguid ESR, Li T, Liu X and McLeod HL (1999) Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian populations. Genomics 58: 310–312
Moertel CG (1994) Chemotherapy for colorectal cancer. N Engl J Med 330: 1136–1142
Peters GJ, Van der Wilt CL, Van Groeningen CJ, Smid K, Meijer S and Pinedo HM (1994) Thymidylate synthase inhibition after administration of fluorouracil with or without leucovorin in colon cancer patients: implications for treatment with fluorouracil. J Clin Oncol 12: 2035–2042
Salonga D, Danenberg KD, Johnson M, Metzger R, Groshen S and Tsao-Wei DD et al (2000) Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6: 1322–1327
Santi DV, McHenry CS and Sommer H (1974) Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxuridylate. Biochemistry 13: 471–481
Soong R and Iacopetta B (1997) A rapid and non-isotopic method for the screening and sequencing of p53 gene mutations in formalin-fixed, paraffin-embedded tumors. Modern Pathology 10: 252–258
Toyota M, Ahuja N, Ohe-Toyota M, Herman J, Baylin S and Issa J-P (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96: 8681–8686
van Triest B, Pinedo HM, van Hensbergen Y, Smid K, Telleman F and Schoenmakers PS et al (1999) Thymidylate synthase level as the main predictive parameter for sensitivity to 5-fluorouracil, but not for folate-based thymidylate synthase inhibitors, in 13 nonselected colon cancer cell lines. Clin Cancer Res 5: 643–654
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Iacopetta, B., Grieu, F., Joseph, D. et al. A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 85, 827–830 (2001). https://doi.org/10.1054/bjoc.2001.2007
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DOI: https://doi.org/10.1054/bjoc.2001.2007
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