Wang X, Sun X, Du X, Zhou F, Yang F, Xing J, Dong G, Guo X
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.
State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169, Changle West Road, Xi'an 710032, China.
Clin Res Hepatol Gastroenterol. 2017 Jun;41(3):319-326. doi: 10.1016/j.clinre.2016.10.012. Epub 2016 Dec 30.
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.
胸苷酸合成酶（TYMS）是叶酸代谢中的关键限速酶，在包括肝细胞癌（HCC）在内的多种恶性肿瘤的发生发展中起重要作用。然而，TYMS基因单核苷酸多态性（SNP）与中国HCC患者预后的关系尚不清楚。
本研究共纳入492例接受手术治疗的HCC患者。使用iPLEX基因分型系统对TYMS基因中的5个功能性SNP（rs2847153、rs2853533、rs502396、rs523230和rs9967368）进行基因分型。采用多因素Cox比例风险回归模型和Kaplan-Meier曲线分析SNP与HCC患者生存和复发的关系。
TYMS基因中的两个SNP（rs523230和rs9967368）与HCC患者的总生存期显著相关。与携带纯合野生型（WW）或杂合子（WV）基因型的患者相比，携带rs523230纯合变异基因型（VV）的患者死亡风险显著降低（风险比[HR]，0.68；95%置信区间[CI]，0.46-1.00；P=0.048），而与携带WW基因型的患者相比，携带rs9967368的WV+VV基因型的患者死亡风险显著增加（HR，1.46；95%CI，1.05-2.04；P=0.026）。累积效应分析显示不利SNP对总生存期有显著的剂量依赖性效应。
我们的研究首次证明了TYMS基因中的SNP与HCC临床结局的关联，提示TYMS基因中的rs523230和rs9967368可用于预测中国HCC患者的临床结局。
