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Thymidylate synthase pharmacogenetics.

Sharon Marsh1

  • 1Division of Molecular Oncology, Washington University School of Medicine in St. Louis, 660, South Euclid Avenue, Campus Box 8069, St. Louis, MO 63110, USA. smarsh@im.wustl.edu

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Genetic variations in thymidylate synthase (TYMS) impact chemotherapy effectiveness. Identifying these TYMS gene polymorphisms can help predict patient response to drugs like 5-fluorouracil and methotrexate, guiding personalized cancer treatment.

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Area of Science:

  • Genetics
  • Pharmacogenomics
  • Oncology

Background:

  • Thymidylate synthase (TYMS) is a key target for chemotherapy agents like 5-fluorouracil (5FU) and methotrexate.
  • Overexpression of TYMS is associated with resistance to these targeted therapies, posing a clinical challenge.
  • Currently, no established protocols exist for pre-treatment selection of cancer patients at risk of developing drug resistance.

Purpose of the Study:

  • To investigate the association between three specific TYMS gene polymorphisms and TYMS expression levels.
  • To explore the relationship between these polymorphisms and patient response to TYMS-targeted chemotherapy.
  • To highlight evidence linking TYMS genetic variations to both gene expression and clinical outcomes in cancer patients.

Main Methods:

  • Analysis of three polymorphisms in the 5' and 3' untranslated regions (UTRs) of the TYMS gene.
  • Correlation of the TSER polymorphism (28 bp tandem repeat in the 5'UTR enhancer region) and a specific SNP (TSER(*)3 allele) with patient response.
  • Assessment of a 6 bp deletion in the 3'UTR of the TYMS gene and its association with TYMS RNA expression and patient outcomes.

Main Results:

  • Preliminary data suggests patients with 3 copies of the TSER polymorphism exhibit poorer response rates to 5FU or methotrexate.
  • The TSER(*)3 allele may further refine the prediction of treatment response in conjunction with the TSER polymorphism.
  • A 6 bp deletion in the TYMS 3'UTR is linked to altered TYMS RNA expression and significantly associated with poor outcomes in patients treated with 5FU.

Conclusions:

  • TYMS gene polymorphisms in the 5'UTR and 3'UTR significantly influence TYMS expression.
  • These genetic variations are associated with patient response and outcomes in TYMS-targeted chemotherapy.
  • Identifying these polymorphisms could lead to improved patient selection for chemotherapy, optimizing treatment efficacy and minimizing resistance.