Genetic Polymorphisms of GSTM1, GSTT1, and GSTP1 with Prostate Cancer Risk: A Meta-Analysis of 57 Studies

and GSTP1 with Prostate Cancer Risk: A Meta-Analysis of 57 Studies. PLoS ONE 7(11): e50587. doi:10.1371/journal.pone.0050587 Genetic Polymorphisms of GSTM1 , GSTT1 , and GSTP1 with Prostate Cancer Risk: A Meta-Analysis of 57 Studies Mancheng Gong 0 Wenjing Dong 0 Zhirong Shi 0 Yangyang Xu 0 Wenjun Ni 0 Ruihua An 0 Rui Medeiros, IPO, Inst Port Oncology, Portugal 0 1 Department of Urological Surgery, The First Affiliated Hospital of Harbin Medical University , Harbin , China , 2 Department of Oncology, The First Affiliated Hospital of Harbin Medical University , Harbin , China , 3 Department of Pharmacy, The Second People's Hospital of Zhuhai , Zhuhai , China , 4 Department of Urological Surgery, The Affiliated Tumor Hospital of Harbin Medical University , Harbin , China , 5 Department of Urological Surgery, The Hei Longjiang Hospital , Harbin , China Background and Objectives: The GSTM1, GSTT1 and GSTP1 polymorphisms might be involved in inactivation of procarcinogens that contribute to the genesis and progression of cancers. However, studies investigating the association between GSTM1, GSTT1 or GSTP1 polymorphisms and prostate cancer (PCa) risk report conflicting results, therefore, we conducted a meta-analysis to re-examine the controversy. Methods: Published literature from PubMed, Embase, Google Scholar and China National Knowledge Infrastructure (CNKI) were searched (updated to June 2, 2012). According to our inclusion criteria, studies that observed the association between GSTM1, GSTT1 or GSTP1 polymorphisms and PCa risk were included. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of PCa associated with GSTM1, GSTT1 and GSTP1 polymorphisms. Results: Fifty-seven studies involving 11313 cases and 12934 controls were recruited. The overall OR, which was 1.2854 (95% CI = 1.1405-1.4487), revealed a significant risk of PCa and GSTM1 null genotype, and the similar results were observed when stratified by ethnicity and control source. Further, the more important is that the present study first reported the high risks of PCa for people who with dual null genotype of GSTM1 and GSTT1 (OR = 1.4353, 95% CI = 1.0345-1.9913), or who with GSTT1 null genotype and GSTP1 A131G polymorphism (OR = 1.7335, 95% CI = 1.1067-2.7152). But no association was determined between GSTT1 null genotype (OR = 1.102, 95% CI = 0.9596-1.2655) or GSTP1 A131G polymorphism (OR = 1.0845, 95% CI = 0.96-1.2251) and the PCa risk. Conclusions: Our meta-analysis suggested that the people with GSTM1 null genotype, with dual null genotype of GSTM1 and GSTT1, or with GSTT1 null genotype and GSTP1 A131G polymorphism are associated with high risks of PCa, but no association was found between GSTT1 null genotype or GSTP1 A131G polymorphism and the risk of PCa. Further rigorous analytical studies are highly expected to confirm our conclusions and assess gene-environment interactions with PCa risk. - . These authors contributed equally to this work. Prostate cancer (PCa) has become a major public health problem concern worldwide for its high morbidity and mortality levels. It is the second leading cause of cancer related to death in Europe, North America, Latin America, and some parts of Africa in men. It has been reported that PCa have a prominent variation in incidence among different ethnic groups and geographic regions. For instance, North Americans have the highest incidence, especially the African-Americans in USA, and the lowest is among Asian men [13]. However, the etiology and ethnic disparities of PCa are largely unknown. Clinical and epidemiologic data suggest that the development of PCa is a multiphase process. So far, a series environmental and lifestyle factors, including pollutants, smoking habit and diet, as well as geographical and racial factors have been pointed out as possible contributors to the risk of PCa [4]. In addition, the various risk, incidence, and mortality rates among worldwide of PCa suggest that genetic factors also play an important role in PCa initiation and progression, such as individual differences in the susceptibility to cancers, age and family history [5]. Therefore, the occurrence and development of PCa most likely involve a complex interplay between genetic and environmental factors. More specifically, variations in carcinogen metabolism genes may play a critical role in PCa development due to their activation or detoxification functions. Glutathione S-transferases (GSTs) constitute a superfamily of ubiquitous, multifunctional phase II metabolic enzymes. These enzymes play a crucial function in the detoxification of both endogenous and exogenous carcinogens [6], but also participate in the activation and inactivation of oxidative metabolites of carcinogenic compounds so that to protect DNA from oxidative damage [7]. Hence, it has been speculated that GSTs were Controlsa BPHa Controlsa BPHa Controlsa BPHa P value for HWE Controlsa BPHa Controlsa BPHa Controlsa BPHa P value for HWE Controlsa BPHa P value for HWE Controlsa BPHa Controlsa BPHa Controlsa BPHa Controlsa BPHa Controlsa BPHa P value for HWE 242/1158 153/583 aNull/present. #Used both healthy people and BPH patients as controls. GSTM1, glutathione S-transferase M1; GSTT1, glutathione S-transferase T1; GSTP1, glutathione S-transferase P1. PB, population-based controls; HB, hospital-based controls; BPH, benign prostate hyperplasia. doi:10.1371/journal.pone.0050587.t001 probably involved in the development of cancers [8]. As the enzymes are widely distributed in nature and found in essentially all eukaryotic species, individual genetic differences may influence the activity level of GSTs and susceptibility to cancer. To date, the GSTs have been assigned to eight distinct classes: a(GSTA),m(GSTM),h(GSTT),p(GSTP),s(GSTS),k(GSTK),o(Gm(GSTM),h(GSTT),p(GSTP),s(GSTS),k(GSTK),o(GSTO),t(GSTZ), while several of them are polymorphic that contain one or more homodimer or heterodimer forms [9,10]. Polymorphisms in these genes, possibly by altering their expression and functional activities, may affect their effect on carcinogen activation/ detoxification and DNA repair. In recent years, GSTM1, GSTT1 and GSTP1 have been studied most. The GSTM1, GSTT1 and GSTP1 gene were located on chromosome 1p13.3, 22q11.23, 11q13 respectively [11,12]. Both GSTM1 and GSTT1 gene exhibit an inherited homozygous deletion polymorphism (null genotype), which has been associated with the loss of enzyme activity and increased vulnerability to cytogenetic damage [13]. As a result of decreased efficiency in protection against carcinogens, the individuals with homozygous deletion polymorphism are considered to be at an increased risk for malignancies [10,14]. Whereas for GSTP1 polymorphism, a single nucleotide polymorphism in exon 5 (Ile105Val, rs1695) received most attention. The A-to-G transition results in an amino acid change from isoleucine to valine so that leading to signi (...truncated)