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A novel G/C single-nucleotide polymorphism in the double 28-bp repeat thymidylate synthase allele

The Pharmacogenomics Journal volume 6, pages 421–424 (2006)Cite this article

Abstract

Thymidylate synthase (TYMS) is the main molecular target for fluoropyrimidine anticancer drugs, and its expression has been correlated with the number of repeats of a 28-bp sequence in the 5′-untranslated region of the TYMS gene and with the presence of a G → C single-nucleotide polymorphism in the second repeat of 3R alleles. Based on this double polymorphism, three main TYMS alleles have so far been identified: TYMS 2R, TYMS 3RC and TYMS 3RG. During genetic analysis of TYMS polymorphisms in 100 colorectal cancer patients, three patients revealed an unexpected 113-bp band after electrophoresis of the restriction fragment length polymorphism analysis. Subsequent sequencing revealed two 28-bp repeats in the 5′-untranslated region and the presence in both repeats of cytosine instead of guanine at the 12th nucleotide. This allele variant (TYMS 2RC) has not been previously described in man. All three patients were heterozygotes for TYMS 2RC and experienced grade 2–3 chemotherapy-related toxicity.

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References

  1. Popat S, Matakidou A, Houlston RS . Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2004; 22: 529–536.

    Article  CAS  PubMed  Google Scholar 

  2. Kawakami K, Salonga D, Park JM, Danenberg KD, Uetake H, Brabender J et al. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 2001; 7: 4096–4101.

    CAS  PubMed  Google Scholar 

  3. Mandola MV, Stoehmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ et al. A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 2003; 63: 2898–2904.

    CAS  PubMed  Google Scholar 

  4. Kawakami K, Watanabe G . Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 2003; 63: 6004–6007.

    CAS  PubMed  Google Scholar 

  5. Graziano F, Kawakami K, Watanabe G, Ruzzo A, Humar B, Santini D et al. Association of thymidylate synthase polymorphism with gastric cancer susceptibility. Int J Cancer 2004; 112: 1010–1011.

    Article  CAS  PubMed  Google Scholar 

  6. Kawakami K, Graziano F, Watanabe G, Ruzzo A, Santini D, Catalano V et al. Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy. Clin Cancer Res 2005; 11: 3778–3783.

    Article  CAS  PubMed  Google Scholar 

  7. Marcuello E, Altes A, Del Rio E, Cesar A, Menoyo A, Baiget M . Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer 2004; 112: 733–737.

    Article  CAS  PubMed  Google Scholar 

  8. O’Connel MJ, Mailliard JA, Kahn MJ, Macdonald JS, Haller DG, Mayer RJ et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997; 15: 246–250.

    Article  Google Scholar 

  9. Miller AB, Hoogstraten B, Staquet M, Winker A . Reporting results of cancer treatment. Cancer 1981; 47: 207–214.

    Article  CAS  PubMed  Google Scholar 

  10. Horie N, Aiba H, Oguro K, Takeishi K . Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene of thymidylate synthase. Cell Struct Funct 1995; 20: 191–197.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The financial support by Lega Italiana per la Lotta Contro i Tumori, Sezione di Rovigo, is acknowledged. Given the public source of funding, no duality of interest is declared.

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Authors and Affiliations

  1. Oncology Unit, Rovigo Hospital, Rovigo, Italy

    M Gusella, C Bolzonella, G Crepaldi & E Ferrazzi

  2. Department of Pharmacology and Anesthesiology, University of Padova, Padova, Italy

    R Padrini

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  1. M Gusella
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  2. C Bolzonella
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  3. G Crepaldi
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  4. E Ferrazzi
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  5. R Padrini
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Correspondence to M Gusella.

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Gusella, M., Bolzonella, C., Crepaldi, G. et al. A novel G/C single-nucleotide polymorphism in the double 28-bp repeat thymidylate synthase allele. Pharmacogenomics J 6, 421–424 (2006). https://doi.org/10.1038/sj.tpj.6500401

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