Prospective Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 14, 2015; 21(14): 4310-4322
Published online Apr 14, 2015. doi: 10.3748/wjg.v21.i14.4310
Polymorphisms of glutathione S-transferase genes and survival of resected hepatocellular carcinoma patients
Kai Qu, Su-Shun Liu, Zhi-Xin Wang, Zi-Chao Huang, Si-Nan Liu, Hu-Lin Chang, Xin-Sen Xu, Ting Lin, Ya-Feng Dong, Chang Liu
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
Ya-Feng Dong, Department of Obstetrics and Gynecology, University of Kansas School of Medicine, Kansas City, KS 66160, United States
Author contributions: Qu K and Liu C designed the research and wrote this paper; Liu SS, Wang ZX and Huang ZC performed the statistical analysis; Liu SN, Chang HL and Xu XS were involved in collecting patient data; Qu K and Lin T took part in literature searches; Dong YF edited the manuscript.
Supported by Grants from National Natural Science Foundation of China, No. 81201549 and No. 81272644; and the Project of Innovative Research Team for Key Science and Technology in Xi’an Jiaotong University, No. 2003KCJ-23.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Chang Liu, MD, PhD, Department of Hepatobiliary Surgery, the First Affiliated Hospital of Medical College, Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an 710061, Shaanxi Province, China. liuchangdoctor@163.com
Telephone: +86-29-82654746 Fax: +86-29-82654746
Received: July 24, 2014
Peer-review started: July 24, 2014
First decision: August 10, 2014
Revised: August 19, 2014
Accepted: October 21, 2014
Article in press: October 21, 2014
Published online: April 14, 2015
Processing time: 265 Days and 7.2 Hours
Abstract

AIM: To investigate the effects of single nucleotide polymorphisms (SNPs) in glutathione S-transferase (GST) genes on survival of hepatocellular carcinoma (HCC) patients.

METHODS: 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.

RESULTS: 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.

CONCLUSION: Our study provides the first evidence that GSTO2 and GSTP1 gene polymorphisms may serve as independent prognostic markers for HCC patients.

Keywords: Glutathione S-transferase; Polymorphism; Hepatocellular carcinoma; Clinical outcome; Surgery

Core tip: To determine the prognostic value of single nucleotide polymorphisms (SNPs) in GST genes in hepatocellular carcinoma (HCC) after liver resection, we analyzed the association between 12 tagging SNPs in GST genes and outcome of 214 HCC patients who underwent liver resection. Our data showed two SNPs (GSTO2: rs7085725 and GSTP1: rs4147581) to be significantly associated with overall survival in HCC patients. These two SNPs used in combination were more powerful prognostic markers for HCC patients. Our study provides the first evidence that GSTO2 and GSTP1 gene polymorphisms may serve as independent prognostic markers for HCC patients.