Colorectal carcinomas with microsatellite instability display increased thymidylate synthase gene expression levels

Abstract

Background: This study investigated whether patients with colorectal cancer (CRC) who have tumors with high microsatellite instability (MSI; MSI-H) had an altered expression of the folate and methyl-group metabolism. The gene expression levels of thymidylate synthase (TS), reduced folate carrier (RFC-1), folylpolyglutamate synthase (FPGS), and methylenetetrahydrofolate reductase (MTHFR) in mucosa and tumor were compared with patients with MSS. Furthermore, the influence of TS polymorphisms on TS gene expression levels and MSI-H was studied.

Patients and methods: The microsatellite status (MSI-H, low instability [MSI-L], or stable [MSS]) and TS polymorphisms were analyzed in genomic DNA from 181 patients with CRC. Gene expression levels of TS, RFC-1, FPGS, and MTHFR in mucosa and tumors were quantified and the difference in TS expression between tumor and mucosa was designated DeltaTS.

Results: Significantly higher gene expression levels of TS (P < .0001) were detected in patients with CRC with MSI-H compared with MSS/MSI-L tumors. Gene expression of TS and FPGS were significantly higher in right-sided MSI-H tumors compared with right-sided MSS/MSI-L tumors (P < .0001, P = .041, respectively). A significant correlation between DeltaTS and the number of unstable markers was found (P < .0001). An inverse association between age and TS expression was found in MSI tumors (r = -0.57; P = .0004) and also in right-sided tumors (r = -0.25, P = .011) regardless of MSI status. No relation was detected between MSI status and the TS polymorphisms or between the TS polymorphisms and TS expression.

Conclusion: This study has revealed, for the first time, that age and the frequency of unstable MSI markers were factors that were linked to the variability in TS gene expression in tumors.