title: Thymidylate synthase gene polymorphisms as important contributors affecting hepatocellular carcinoma prognosis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169, Changle West Road, Xi'an 710032, China; Department of Breast Cancer Center, Shaanxi Cancer Hospital, Xi'an 710061, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169, Changle West Road, Xi'an 710032, China.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169, Changle West Road, Xi'an 710032, China.
authors.forename: X
authors.initials: X
authors.lastname: Du
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169, Changle West Road, Xi'an 710032, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169, Changle West Road, Xi'an 710032, China.
authors.forename: F
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169, Changle West Road, Xi'an 710032, China.
authors.forename: J
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of General Surgery, The General Hospital of PLA, 28, Fuxing Road, Beijing 100853, China. Electronic address: guanglongdong@126.com.
authors.forename: G
authors.initials: G
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169, Changle West Road, Xi'an 710032, China. Electronic address: fmmuxguo@163.com.
authors.forename: X
authors.initials: X
authors.lastname: Guo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006785:Hospitals, University; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C000600377:TYMS protein, human; D013940:Thymidylate Synthase