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Association of thymidylate synthase enhancer region polymorphisms with thymidylate synthase activity in vivo

The Pharmacogenomics Journal volume 11, pages 307–314 (2011)Cite this article

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Abstract

Two known polymorphisms in the 5′ enhancer region (ER) of the thymidylate synthase (TS) gene, a variable number of tandem repeats of a 28 bp sequence (2R/3R) and a further G>C single nucleotide substitution within the repeats, result in genotypes with 0–5 functional upstream stimulatory factor (USF) E-box consensus elements. However, the relationship between these polymorphisms, regulation of TS expression and patient response to fluoropyrimidine treatment has been inconsistent. In this study, seven possible TSER allele configurations showed similar patterns of luciferase gene expression regardless of cell type or USF-1 content, with no significant difference in promoter activity between the wild-type 2RGC and 3RGGC (1.40±0.37 vs 1.43±0.32, P=0.90), whereas the minor alleles, 2RCC and 3RGCC, were significantly reduced (0.84±0.17, P=0.01) and increased (3.19±0.72, P=0.001) respectively. Patient plasma levels of 2′-deoxyuridine, a surrogate marker of TS activity, were significantly different between genotypes (P<0.001) and inversely related to luciferase activity (P=0.02) but not to the absolute number of functional repeated elements (P=0.16), suggesting that the position, rather than the number of functional USF E-box repeats in the TSER, is responsible for determining gene expression in vitro and TS activity in vivo.

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Acknowledgements

This work was supported by funding from the Margaret Mitchell and Jane Reid Harle Memorial Grant Schemes, Calvary Mater Newcastle, New South Wales.

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Authors and Affiliations

  1. Division of Cancer and Cell Biology, Leukaemia Foundation Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    C E de Bock

  2. Hunter Medical Research Institute, Newcastle, New South Wales, Australia

    C E de Bock, M B Garg, N Scott, J A Sakoff, F E Scorgie, S P Ackland & L F Lincz

  3. Department of Medical Oncology, Calvary Mater Newcastle Hospital, Waratah, New South Wales, Australia

    M B Garg, J A Sakoff & S P Ackland

  4. Faculty of Health, School of Biomedical Sciences, University of Newcastle, Newcastle, New South Wales, Australia

    N Scott, S P Ackland & L F Lincz

  5. Hunter Haematology Research Group, Calvary Mater Newcastle Hospital, Waratah, New South Wales, Australia

    F E Scorgie & L F Lincz

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  1. C E de Bock
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  2. M B Garg
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Correspondence to L F Lincz.

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de Bock, C., Garg, M., Scott, N. et al. Association of thymidylate synthase enhancer region polymorphisms with thymidylate synthase activity in vivo. Pharmacogenomics J 11, 307–314 (2011). https://doi.org/10.1038/tpj.2010.43

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