Thymidylate Synthase Gene Polymorphism as a Prognostic Factor for the Colorectal Cancer

Purpose: Thymidylate synthase (TS) expression in colorectal-tal cancer is regarded as both a prognostic marker and a predictor of response to fluoropyrimidine-based therapies targeting TS. However, results from immunohistochemical staining of TS show wide discrepancies. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here, we determined the significance of this polymorphism in predicting the clinical outcomes for patients with operable colorectal cancer treated by a curative resection. Methods: The cases of 121 patients with stage II or III colorectal cancer, who underwent a curative resection, were reviewed. After DNA extraction from paraffinembedded tissues, the promoter region of the TS gene was amplified by polymerase chain reaction. Results: Sixty-eight subjects were homozygotes for the triple repeat variant (group A, L/L, 250-bp), and 53 subjects (group B) were either homozygotes for the double repeat variant (S/S, 220-bp) or heterozygotes (S/L, 220 and 250-bp). The difference between stage II and stage III patients was significant with regard to the 5-year actuarial survival (87% vs 63%, P=0.0320). Examining the survival according to the TS polymorphism, we found a significant difference between group A and B (80% vs 53%, P=0.0481). In patients with stage II disease, the difference in survival rates between group A and B did not reach statistical significance (43% vs 86%, P=0.1678). However, the difference was significant between group A and B for stage III disease (77% vs 41%, P=0.0414). Conclusions: We found the TS polymorphism to be a significant and independent prognostic factor for operable colorectal cancer. We think assay of the TS polymorphism can overcome the technical pitfalls of immunohistochemical staining and give more solid prognostic information in the treatment of colorectal cancer.