Thymidylate synthase polymorphisms are associated with survival among colorectal cancer patients

Proc Amer Assoc Cancer Res, Volume 46, 2005 2563 Folate metabolism is the target of folate antagonists and thymidylate synthase (TS) inhibitors, such as 5-fluorouracil (5-FU), a widely used cancer chemotherapeutic agent. However, only a subset of patients responds to 5-FU therapy, suggesting that functional polymorphisms in TS and 5,10-methylene-tetrahydrofolate reductase ( MTHFR ) may modify its effectiveness. We examined possible differences in survival among colorectal cancer patients depending on TS genotypes (a repeat polymorphism in the promoter enhancer region, TSER , and a deletion in the 3’UTR,1494del6, which are associated with reduced gene expression or mRNA stability) and MTHFR genotypes (C677T and A1298C, both associated with reduced enzyme activity). Study Design: 745 incident colorectal cancer patients, diagnosed with regional or distant stages and who received chemotherapy, were identified in the Seattle, Washington area through the population-based SEER registry between 1998-2002. Subjects completed telephone interviews to collect exposure information on supplemental folate use (from multivitamins and other supplements), demographics, and other risk factors. Stage at diagnosis and treatment were obtained by SEER. All participants were passively followed for mortality until 9/2004. After an average of 33.7 months of follow-up time, 219 cases were deceased. Age- and stage-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were obtained using Cox-proportional hazards regression. Results: Compared to the reference group of individuals with wildtype genotypes for both TSER (3rpt/3rpt) and 3’UTR (6bp/6bp), there was a suggestion that individuals who had a genotype with at least one 2rpt allele had a modestly increased risk of death (HR=1.6, 95% CI: 0.9-2.7); similar results were seen with at least one 6bp deletion at bp1494 (HR=1.6, 95% CI: 0.9-2.6). When examining the combined TS genotypes (=diplotypes), individuals who were heterozygous for both polymorphisms had an almost two-fold increased risk (HR=1.8, 95% CI: 1.02-3.2); in general, all individuals with variant TS alleles - conferring reduced TS expression - were at increased risk of death compared to those that were wildtype at both loci. TS genotype results differed by prior use of supplemental folate; increased risk of death with any variant TS genotype was only observed among individuals who had ever used folate/multivitamin supplements (ever users: OR=2.5, 95% CI: 1.3-5.0, never users: OR=0.58, 95% CI: 0.23-1.42). Survival did not differ by MTHFR genotypes. Conclusions: Results from this study suggest that polymorphisms in the TS gene may affect survival after colorectal cancer diagnosis, possibly by diverting 5,10-methylene-tetrahydrofolate towards purine synthesis fostering tumor growth. Pharmacogenetic mechanisms are less likely to explain these trends. Intriguingly, this relationship may be modified by the use of folate supplements.