The Glutathione S-Transferase P1 341C>T Polymorphism and Cancer Risk: A Meta-Analysis of 28 Case-Control Studies

et al. (2013) The Glutathione S-Transferase P1 341C.T Polymorphism and Cancer Risk: A Meta-Analysis of 28 Case-Control Studies. PLoS ONE 8(2): e56722. doi:10.1371/journal.pone.0056722 The Glutathione S-Transferase P1 341C.T Polymorphism and Cancer Risk: A Meta-Analysis of 28 Case-Control Studies Sheng-xin Huang 0 Fei-xiang Wu 0 Min Luo 0 Liang Ma 0 Ke-feng Gao 0 Jian Li 0 Wen-juan Wu 0 Shan Huang 0 Qi Yang 0 Ke Liu 0 Yin-nong Zhao 0 Le-qun Li 0 Giuseppe Novelli, Tor Vergata University of Rome, Italy 0 1 Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University , Nanning , People's Republic of China, 2 Department of Experiment, Affiliated Tumor Hospital of Guangxi Medical University , Nanning , People's Republic of China, 3 Department of Thoracic Surgery, Affiliated Tumor Hospital of Guangxi Medical University , Nanning , People's Republic of China, 4 Department of Gynecologic Oncology, Affiliated Tumor Hospital of Guangxi Medical University , Nanning , People's Republic of China Background: GSTP1, which is one major group of the glutathione S-transferase family, plays an important role in the metabolism of carcinogens and toxins, reducing damage of DNA as a suppressor of carcinogenesis. The 341C.T polymorphism of the GSTP1 has been implicated in cancer risk through cutting down its metabolic detoxification activities. However, results from previous studies remain conflicting rather than conclusive. To clarify the correlation and provide more statistical evidence for detecting the significance of 341C.T, a meta-analysis was conducted. Methodology/Principal Findings: The relevant studies were identified through searching of PubMed, Embase, ISI Web of Knowledge and China National Knowledge Infrastructure in August 2012, and selected based on the established inclusion criteria for publications, then a meta-analysis was performed to quantitatively summarize the association of GSTP1 341C.T polymorphism with cancer susceptibility. Stratified analyses were employed to identify the source of heterogeneity. Publication bias was evaluated as well as sensitivity analysis. Based on 28 case-control studies with 13249 cases and 16798 controls, the pooled results indicated that the variant genotypes significantly increased the risk of cancer in homozygote comparison (TT versus CC: P = 0.012, OR = 1.40, 95% CI: 1.08-1.81, Phet. = 0.575), and recessive model (TT versus CT/CC: P = 0.012, OR = 1.40, 95% CI: 1.08-1.81, Phet. = 0.562). This was confirmed when stratified analyses were conducted according to ethnicity, source of control, matched control, quality score and cancer types. Moreover, significantly increased risk of cancer was also found in lung cancer (heterozygote comparison and dominant model). The stability of these observations was confirmed by a sensitivity analysis. Begger's funnel plot and Egger's test did not reveal any publication bias. Conclusions/Significance: This meta-analysis suggests that the GSTP1 341C.T polymorphism may contribute to genetic susceptibility to cancer, especially to lung cancer, and in Asian population. Nevertheless, additional well-designed studies focusing on different ethnicity and cancer types are needed to provide a more exact and comprehensive conclusion. - . These authors contributed equally to this work. Approximately 12.7 million new cases of cancer, and 7.6 million cancer-related deaths occurred in 2008, which indicated global burden of cancer continues to aggravate [1]. Prevention and diagnosis of cancer have become one of the most important challenges of the world. Potent markers for screening high-risk populations are urgently needed for early detection and preventive actions. The development of cancer is a complicated biological process, which is involved with multi-gene mutations and multiple factors, while the individual hereditary background may be the primarily determined risk of cancer susceptibility. The interaction between genetic susceptibility genes with environmental factors and metabolism dysfunction throughout the body plays an important role in the development of cancer [2]. The glutathione S-transferase family (GSTs), which are composed of four major groups including GSTA (a), GSTM1 (m), GSTT1 (h), and GSTP1 (p), are phase II detoxifying enzymes that catalyze a variety of reduced glutathione-dependent reactions with electrophilic substrates [3]. Based on the catalytic activity, GSTs metabolize carcinogens and toxins to reduce damage of DNA as a suppressor of carcinogenesis. The risk of cancer is correlated with exposure to xenobiotics or endogenous substances, which may be modified in metabolic detoxification activities by genetic variation [4]. It is well known that deletion variants of the GSTM1, GSTT1 and GSTP1 loci could result in loss of functional activity. Hendersonet et al. [5] found that GSTP1 null mice, disposed with carcinogen polycyclic aromatic hydrocarbons, had a highly significantly increased risk of skin cancer, anddemonstrated that GSTP1 may be an important determinant in cancer susceptibility. Chromosomal polymorphisms in genes involved in DNA repair, cell cycle control, apoptosis or metabolic enzymes may determine individual susceptibility to cancer [6]. Variants of prevalent allele in every GSTs gene may lower the efficiency of detoxification and aggravate the susceptibility to cancer. It was identified that there are two single nucleotide polymorphisms in GSTP1 that lead to changes in amino acids. One at nucleotide 313 (codon 104) in exon 5 (rs1695) has an A to G transition, which results in an amino acid change from isoleucine (Ile) to valine (Val). The other has a C to T transition in nucleotide 341 (codon 113) in exon 6 (rs1138272) which results in an amino acid change from alanine (Ala) to valine (Val) (Figure S1). This two loci were reported to cause minimal catalytic activity in individuals who carry one or more copies of the allele G or T [7,8]. A large number of studies have investigated the role of GSTP1 polymorphism in the etiology of cancer of various organs, including lung, breast, colorectal, bladder, prostate and so on. However, most of these studies contained small number of subjects, and the results of these studies remain conflicting rather than conclusive. In recent years, plenty of meta-analysis studies were extensively carried out to quantitatively evaluate the association between GSTP1 and cancer susceptibility. As a consequence, statistically significant increased risk was found between GSTP1 313A.G and breast cancer [9], esophageal cancer [10], bladder cancer [11], leukemia [12] and other cancers. Nevertheless, no pooled evaluation on GSTP1 341C.T has been performed yet. In light of the ubiquity of 341C.T polymorphism and the critical role of GSTP1 in the carcinogenic process, we performed a meta-analysis on all eligible case-control studies to estimate the cumulative cancer risk of this polymorphism, and quantitatively analyze the pote (...truncated)