Qu Kai, Liu Su-Shun, Wang Zhi-Xin, Huang Zi-Chao, Liu Si-Nan, Chang Hu-Lin, Xu Xin-Sen, Lin Ting, Dong Ya-Feng, Liu Chang
Kai Qu, Su-Shun Liu, Zhi-Xin Wang, Zi-Chao Huang, Si-Nan Liu, Hu-Lin Chang, Xin-Sen Xu, Ting Lin, Chang Liu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
World J Gastroenterol. 2015 Apr 14;21(14):4310-22. doi: 10.3748/wjg.v21.i14.4310.
To investigate the effects of single nucleotide polymorphisms (SNPs) in glutathione S-transferase (GST) genes on survival of hepatocellular carcinoma (HCC) patients.
Twelve tagging SNPs in GST genes (including GSTA1, GSTA4, GSTM2, GSTM3, GSTO1, GSTO2 and GSTP1) were genotyped using Sequenom MassARRAY iPLEX genotyping method in a cohort of 214 Chinese patients with resected HCC. The Cox proportional hazards model and log-rank test were performed to determine the SNPs related to outcome. Additionally, stratified analysis was performed at each level of the demographic and clinical variables. An SNP-gene expression association model was further established to investigate the correlation between SNP and gene expression.
Two SNPs (GSTO2: rs7085725 and GSTP1: rs4147581) were significantly associated with overall survival in HCC patients (P = 0.035 and 0.042, respectively). In stratified analysis, they were more significantly associated with overall survival in patients with younger age, male gender and cirrhosis. We further investigated cumulative effects of these two SNPs on overall survival in HCC patients. Compared with the patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 1.70-fold increased risk of death (P < 0.001). The cumulative effects were more significant in those patients with younger age, male gender and cirrhosis (HR = 2.00, 1.94 and 1.97, respectively; all P < 0.001). Additionally, we found that heavy smoking resulted in a significantly worse overall survival in those patients carrying variant alleles of rs7085725 (HR = 2.07, 95%CI: 1.13-3.76, P = 0.018). The distributions of GSTO2: rs7085725 and GSTP1: rs4147581 genotypes were associated with altered gene expression and contributed to influences on overall survival.
Our study provides the first evidence that GSTO2 and GSTP1 gene polymorphisms may serve as independent prognostic markers for HCC patients.
研究谷胱甘肽S-转移酶（GST）基因中的单核苷酸多态性（SNP）对肝细胞癌（HCC）患者生存的影响。
采用Sequenom MassARRAY iPLEX基因分型方法，对214例接受手术切除的中国HCC患者队列中的GST基因（包括GSTA1、GSTA4、GSTM2、GSTM3、GSTO1、GSTO2和GSTP1）中的12个标签SNP进行基因分型。采用Cox比例风险模型和对数秩检验来确定与预后相关的SNP。此外，在人口统计学和临床变量的每个水平上进行分层分析。进一步建立SNP-基因表达关联模型，以研究SNP与基因表达之间的相关性。
两个SNP（GSTO2：rs7085725和GSTP1：rs4147581）与HCC患者的总生存显著相关（P值分别为0.035和0.042）。在分层分析中，它们在年龄较小、男性和有肝硬化的患者中与总生存的相关性更显著。我们进一步研究了这两个SNP对HCC患者总生存的累积影响。与不携带不利基因型的患者相比，携带2种不利基因型的患者死亡风险增加了1.70倍（P<0.001）。在年龄较小、男性和有肝硬化的患者中，累积影响更显著（HR分别为2.00、1.94和1.97；均P<0.001）。此外，我们发现重度吸烟导致携带rs7085725变异等位基因的患者总生存显著更差（HR=2.07，95%CI：1.13-3.76，P=0.018）。GSTO2：rs7085725和GSTP1：rs4147581基因型的分布与基因表达改变相关，并对总生存产生影响。
我们的研究首次提供证据表明，GSTO2和GSTP1基因多态性可能作为HCC患者的独立预后标志物。
