Involvement of gene polymorphisms of thymidylate synthase in gene expression, protein activity and anticancer drug cytotoxicity using the NCI-60 panel.

ABSTRACT

A significant association has been established, in clinical studies, between the expression or activity of thymidylate synthase (TYMS) and the efficiency of fluorouracil. TYMS expression is partly under the dependence of gene polymorphisms in the 5' and 3' untranslated regions (UTR), but conflicting results have been obtained about their roles on fluorouracil efficiency. In this study, we wanted to use the National Cancer Institute (NCI) panel of 60 human tumour cell lines to clarify this problem. Three relevant polymorphisms of the TYMS gene were studied (i) the 5'UTR tandem repeat of 28-bp (2R/3R polymorphism); (ii) the single nucleotide polymorphism (SNP) within the second repeat (3C/3G polymorphism); (iii) the 3'UTR 6-bp deletion (+6/-6 polymorphism). Allele frequencies were close to those expected in a Caucasian population (2R/3C/3G 53/29/18%; +6/-6 68/32%), but the proportion of heterozygous genotypes was lower than expected from allele frequencies. The 2R and 3G alleles were significantly associated with the +6 and the -6 alleles, respectively. There was a significant association between the presence of the 3G allele and TYMS mRNA expression and catalytic activity, particularly in p53-mutated cell lines. However, no significant correlation existed between fluorouracil cytotoxicity, as extracted from the NCI databases, and TYMS expression, activity or polymorphisms.