Polymorphic tandem repeats in the thymidylate synthase gene correlate with thymidylate synthase activity in normal tissues but not in malignant tissues of colorectal cancer patients

4742 Thymidylate synthase (TS) is the target enzyme of 5-fluorouracil (5-FU). High expression of TS has been related to a poor response of colorectal cancer patients to treatment with 5-FU. The enhancer region of the TS gene (TSER) contains a tandem repeat polymorphism that is thought to influence TS expression and might thereby predict response to 5-FU-based treatment: the triple repeat (TSER 3/3) genotype might be associated with higher TS levels and worse survival than the double repeat (TSER 2/2) or heterozygous (TSER 2/3) genotype. Most studies thus far focused on the relation between TS genotype and survival of patients treated with 5-FUbased chemotherapy. Only few studies explored the relation between TS genotype and in vivo TS expression. These previous studies were limited to tumors. This study comprises a retrospective analysis of the TSER polymorphism in normal (liver, mucosa) and malignant (primary tumor and liver metastasis) tissues of 83 patients with advanced colorectal cancer, to explore the relationship between TSER genotype and TS enzyme level (FdUMP-binding, catalytic activity) and mRNA expression. We found 38 patients with the 2R/3R genotype, 23 with the 2R/2R and 22 with the 3R/3R variant. Confirming previous studies we found a high level of homology (97%) between the TS polymorphic status of normal and malignant tissues from the same patients. In malignant tissues no correlation between TSER genotype and TS protein and mRNA levels was observed. In contrast, in normal tissues we found significantly higher TS protein levels (2.4-fold; p = 0.008) and catalytic activity (2.7-fold; p