Polymorphism in the Thymidylate Synthase Promoter Enhancer Region Modifies the Risk and Survival of Colorectal Cancer

A novel 6-bp deletion in the 3'UTR of the TS gene (TS1494del6) has been identified. It was reported that individuals carrying one or two variant alleles (-6bp, 6-bp deleted) had 40% increased risk of colon cancer (odds ratio, 1.4; 95% CI, 0.99-1.98) compared with those with the homozygous wild-type genotype (+6bp, 6 bp present). Additionally, the tumor mRNA levels in patients with homozygous wild-type genotype (+6bp/+6bp) were reported to be 4.2-fold higher compared with those of patients with homozygous variant genotype (-6bp/-6bp). In this study, we simultaneously examined the effect of both TS polymorphisms on the risk and survival of CRC in the prospective Physicians' Health Study. We also investigated whether these polymorphisms modified the risk and survival of CRC through its influences on plasma folate and tHcy levels. Interpretive Summary: Thymidylate synthase is an enzyme which is uses the vitamin folic acid for its activity. It is responsible for making Thymidine, one of the 4 bases of DNA. The present study was undertaken to determine how variations in the gene that codes for thymidylate synthase affect the risk of developing colorectal cancer and chances of survival for those who will have this cancer. Differences between people are segments in the genes that are repeated three times or two times. We found that people that have only 2 repeats have a lower risk to develop colorectal cancer and have a greater chance of survival than people who have 3 repeats of this segment. This study provides interpretation as to the gene nutrient interaction and relationship to health outcomes. Technical Abstract: Thymidylate synthase (TS) converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. It is also the target for 5-flurorouracil, the most common chemotherapy agent for treatment of colorectal cancer (CRC). We designed a nested case-control study within the prospective Physicians' Health Study to investigate whether TS polymorphisms independently predict risk of CRC and simultaneously the overall survival after the disease in the same population. We also investigated influences of this polymorphism on plasma folate and homocysteine levels. The study consists of 270 incident CRC and 454 control subjects. Risk of CRC was estimated by use of conditional multiple logistic regression analysis. Survival was analyzed by Cox proportional hazards regression analysis. Compared with the TS 3R/3R genotype, the multivariate-adjusted risk ratio was 0.86 (0.59'1.25) for the 2R/3R genotype and 0.59 (0.36'0.98) for the 2R/2R genotype with P for trend of 0.03. The TS 2R/2R genotype was also associated with better survival, although the results were not significant. Compared with those with either the 3R/3R or 2R/3R genotypes, the age-adjusted hazard ratio for the 2R/2R genotype was 0.57 (0.30'1.07). Individuals with the 2R/2R genotype had significantly lower plasma folate levels than those with the 3R/3R genotype, whereas their plasma homocysteine levels were unaffected by the TS promoter polymorphism. The deletion polymorphism at the TS 3'-untranslated region did not influence the CRC risk and survival, nor did it modify the plasma folate and total homocysteine levels. Given that individuals with high plasma folate had a better survival outcome with a hazard ratio of 0.68 (0.45'1.03) compared with those with low plasma folate, we conclude that the TS promoter polymorphism may modify both the risk and the survival of CRC; however, these effects do not appear to be mediated through its modulation of biological folate levels.