Thymidylate synthase gene polymorphisms as important contributors affecting hepatocellular carcinoma prognosis

Abstract

Thymidylate synthase (TYMS), a key rate-limiting enzyme in the folate metabolism, plays essential roles in the development of several malignancies including hepatocellular carcinoma (HCC). Nonetheless, the association of the single nucleotide polymorphisms (SNPs) in TYMS gene with the prognosis of Chinese HCC patients remains unknown. A total of 492 HCC patients who underwent surgery treatment were included in this study. Five functional SNPs (rs2847153, rs2853533, rs502396, rs523230, and rs9967368) in TYMS gene were genotyped using the iPLEX genotyping system. Multivariate Cox proportional hazards regression model and Kaplan-Meier curve were used to analyze the association of SNPs with survival and recurrence of HCC patients. Two SNPs (rs523230 and rs9967368) in TYMS gene were significantly associated with the overall survival of HCC patients. Patients carrying homozygous variant genotype (VV) of rs523230 had significantly decreased risk of death (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.46-1.00; P=0.048) when compared with those carrying homozygous wild-type (WW) or heterozygous (WV) genotypes, while patients carrying WV+VV genotype of rs9967368 had significantly increased risk of death (HR, 1.46; 95% CI, 1.05-2.04; P=0.026) when compared with those carrying WW genotypes. Cumulative effect analysis showed a significant dose-dependent effect of unfavorable SNPs on OS. Our study for the first time demonstrates the association of SNPs in TYMS gene and clinical outcome of HCC, suggesting that rs523230 and rs9967368 in TYMS gene might be used to predict clinical outcome of Chinese HCC patients.