Thymidylate synthase pharmacogenetics

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.