Abstract
Inhibition of thymidylate synthase (TS) is the primary mode of action for 5-fluorouracil (5FU) chemotherapy. TS expression is modulated by a variable number of tandem repeats in the TS enhancer region (TSER) located upstream of the TS gene (TYMS). Variability in the TSER has been suggested to contribute to 5FU-induced adverse events. However, the precise genetic associations remain largely undefined due to high polymorphism and ambiguity in defining genotypes. To assess toxicity associations, we sequenced the TSER in 629 cancer patients treated with 5FU. Of the 13 alleles identified, few could be unambiguously named using current TSER-nomenclature. We devised a concise and unambiguous systematic naming approach for TSER-alleles that encompasses all known variants. After applying this comprehensive naming system to our data, we demonstrated that the number of upstream stimulatory factor (USF1-)binding sites in the TSER was significantly associated with gastrointestinal toxicity in 5FU treatment.
Highlights
As the only de novo source of thymidylate, thymidylate synthase (TS) has a major role in DNA replication through catalyzing the conversion of deoxyuridine-monophosphate to deoxythymidine-monophosphate, a precursor of deoxythymidine-triphosphate
Thirteen unique TS enhancer region (TSER)-variants were identified among the 1258 sequenced alleles (Table 2)
Those alleles could not be classified unambiguously according to the commonly used repeat number” (RN-)nomenclature of TSER-polymorphisms that is based on scoring the apparent number of tandem repeats (Figure 1B, Table 2)
Summary
As the only de novo source of thymidylate, thymidylate synthase (TS) has a major role in DNA replication through catalyzing the conversion of deoxyuridine-monophosphate to deoxythymidine-monophosphate (dTMP), a precursor of deoxythymidine-triphosphate. Thymidylate synthase gene (TYMS) expression levels are low in resting phase cells and high in proliferating cells [1]. Inhibition of TS in proliferating cells leads to severe DNA damage, eventually resulting in cell death [2] and, represents an enticing therapeutic target in cancer. Fluorodeoxyuridine-monophosphate, a metabolite of 5FU, forms a stable ternary complex with TS and the co-factor 5,10-methylene tetrahydrofolate, resulting in inhibition of dTMP synthesis. The subsequent imbalance of the nucleotide pool leads to DNA damage and apoptosis [2].
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