GSTP1 Ile105Val Polymorphism and Prostate Cancer Risk: Evidence from a Meta-Analysis

Abstract

Background

Glutathione S-transferase P1 (GSTP1) is thought to be involved in the detoxification of reactive carcinogen metabolites. Numerous epidemiological studies have evaluated the association of GSTP1 Ile105Val polymorphism with the risk of prostate cancer. However, the results remain inconclusive. To derive a more precise estimation, a meta-analysis was performed.

Methodology/Principal Findings

A comprehensive search was conducted to identify the eligible studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the relationship. The overall association was not significant (Val/Val vs. Ile/Ile OR = 1.06, 95% CI = 0.90–1.25, P = 0.50; Val/Val vs. Val/Ile+Ile/Ile: OR = 1.07, 95% CI = 0.91–1.25, P = 0.44). In subgroup analyses by ethnicity and prostate cancer grade, the similar results were observed. However, in stratified analysis by clinical stage, we found a significant association with low-stage prostate cancer (Val/Val vs. Ile/Ile: OR = 2.70, 95% CI = 1.73–4.22, P<0.001; Val/Val vs. Val/Ile+Ile/Ile: OR = 2.14, 95% CI = 1.38–3.33, P = 0.001). Moreover, there was no statistically significant evidence of multiplicative interactions neither between the GSTP1 Ile105Val polymorphism and GSTM1, nor between smoking status and GSTP1 on prostate cancer risk.

Conclusions

This meta-analysis showed that GSTP1 Ile105Val polymorphism might not be significantly associated with overall prostate cancer risk. Further stratified analyses showed a significant association with low-stage prostate cancer.

About the Authors:

Bingbing Wei

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

You Zhou

Affiliation: Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland

Zhuoqun Xu

* E-mail: [email protected] (ZX); [email protected] (JR)

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Jun Ruan

* E-mail: [email protected] (ZX); [email protected] (JR)

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Huan Cheng

Affiliation: Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Ming Zhu

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Qiang Hu

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Ke Jin

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Zhiqiang Yan

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Deqi Zhou

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Feng Xuan

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Hongyi Zhou

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Zhirong Wang

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Xing Huang

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Qiang Wang

Affiliation: Department of Urology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, China

Introduction

Prostate cancer is the sixth most common cancer in the world, the third most common cancer in men, and the most common cancer in men in Europe, North America, and some parts of Africa [1]. In the United States, it is the second leading cause [2].http://en.wikipedia.org/wiki/Prostate_cancer. Several risk factors for prostate cancer have been identified, such as age, hormones, dietary factors and so on [1]. However, the definitive cause has yet to be elucidated [3]. Current studies suggest that both genetic and environmental factors may influence the pathogenesis of prostate cancer [4]. Numerous studies have shown that glutathione S-transferases (GSTs) are involved in the development of different cancers [5].

Glutathione-S-transferases (GSTs) are phase II enzymes which have been thought to be responsible for catalyzing the biotransformation of multiple electrophilic compounds [6]. It suggests that GSTs have a vital role in the detoxification of activated metabolites of procarcinogens produced by phase I reactions. In humans, eight gene families encode the cytosolic soluble GSTs namely, alpha (GSTA), mu (GSTM), theta (GSTT), pi (GSTP), sigma (GSTS), zeta (GSTZ), kappa (GSTK) and Omega (GSTO) [7]. Among them, several classes of GST enzymes, such as Pi, Alpha, Mu, and Theta, are expressed in prostate tissue, with Pi being the most abundant [8]. The polymorphisms in GSTM1 and GSTT1 are due to homozygous genetic deletions, which could result in absence of the GST enzyme activity, and might increase cancer susceptibility [6]. In contrast to most cancers [9], prostate cancer is associated with marked downregulation of GSTP1. GSTP1 may play a vital role in the development of prostate cancer [10], [11].

GSTP1 is thought to play an important role in susceptibility to prostate cancer. In prostate tissue, it is predominantly expressed in the basal layer of the normal prostate epithelium. Although these normal prostate secretory cells do not routinely express GSTP1, they still retain the capability to express this enzyme [12]. It is found that GSTP1 expression is increased in secretory cells of atrophic prostate epithelium, suggesting that the enzyme remains inducible in this cellular compartment. In addition, its expression is markedly diminished in an overwhelming majority of prostate cancer and prostatic intraepithelial neoplasia (PIN) specimens [13]–[15]. It is speculated that the early loss of GSTP1 function may lead to increased vulnerability to oxidant and heterocyclic amine carcinogens which are implicated in prostate carcinogenesis. Hence, it is possible that the heritable difference in GSTP1 function, due to GSTP1 genetic polymorphism, might be associated with prostate carcinogenesis.

A single nucleotide polymorphism (SNP) in the coding sequence at codon 105 (Ile105Val) of GSTP1 was reported to lower enzymatic activity in vitro [16]. It appears that the decreased detoxification capacity by reduced enzymatic activity may increase susceptibility to prostate cancer. In recent years, the association of GSTP1 Ile105Val polymorphism with prostate cancer risk has been extensively investigated [17]–[43]. One study showed that the frequency of GSTP1 Val/Val genotype was 14.3% in prostate cancer cases compared with 2.4% in controls, providing a notion that there is a significant association (OR: 3.72, 95% CI: 1.67–5.65; P = 0.002) [44]. Lavender et al. [17] observed a moderately significant association among men (OR = 1.56; 95%CI = 0.95–2.58; P = 0.049) and further confirmed it by MDR (multifactor dimensionality reduction) permutation testing (P = 0.001). However, other studies [18], [42] did not show significant results. In addition, GSTM1 have been extensively investigated in the last years. The GSTP1-GSTM1 interaction was also investigated in several studies [22], [24], [26], [31].

On the whole, the results about the association between GSTP1 Ile105Val polymorphism and prostate cancer risk were conflicting and inconclusive. To derive a more precise estimation, we performed a meta-analysis.

Materials and methods

Identification and Eligibility of Relevant Studies

PubMed (1956 to 20 June 2013), EMBASE (1974 to 20 June 2013), HuGENet (2000 to 20 June 2013), and Chinese National Knowledge Infrastructure (CNKI) (1978 to 20 June 2013) database searches were performed using the following terms: “GSTP1”, “polymorphism”, and “prostate”. The references of the retrieved articles were also screened. In case of studies with overlapping data, we selected the study with the largest number of subjects. The studies included in the meta-analysis should meet the following criteria: (a) evaluate the association of GSTP1 Ile105Val polymorphism with prostate cancer risk published in English or Chinese language, (b) use a case-control design, (c) provide the sample size, distribution of alleles, genotypes or other information that contribute to infer study characteristics, and (d) the distribution of GSTP1 genotypes in controls being consistent with Hardy-Weinberg equilibrium (HWE).

Data Extraction

Two authors independently collected the information and reached consensus on all items. The following characteristics were extracted from eligible studies: name of first author, year of publication, country, ethnicity, numbers of genotyped prostate cancer cases and controls. Different ethnic descents were categorized as Caucasians, Asians, and Africans. If a study did not state the ethnic descendent or was not possible to separate participants according to their phenotype, the group [42] was termed “mixed ethnicity”.

Two studies [30], [39] only provided the information on genotypes as “Val/Val+Ile/Val” and “Ile/Ile” without details, so we could only calculate the odds ratio (OR) for the dominant genetic model. In subgroup analyses according to smoking status and GSTM1 null/present genotypes, the studies [22], [24]–[26], [30], [31], [42], [43] provided the information of genotypes as “Ile/Ile” and “Val/Val+Ile/Val”, and we calculated the OR for the dominant genetic model.

Statistical Analysis

The strength of the association between GSTP1 Ile105Val polymorphism and prostate cancer risk was measured by ORs with 95% confidence intervals (CIs). We first estimated the effects of the Val/Val and Val/Ile genotypes on the risk of prostate cancer, compared with the wild-type Ile/Ile homozygote, then evaluated the effects of “Val/Val+Val/Ile vs. Ile/Ile” and “Val/Val vs. Val/Ile+Ile/Ile” on the risk, in dominant and recessive models, respectively. Subgroup analyses were also performed based on clinical stage, grade, ethnicity, smoking status, and GSTM1 null/present genotype.

Between studies heterogeneity was evaluated with the Q test based on the Chi-square distribution (P<0.10 was considered significant) [45], [46]. In case of heterogeneity, the random effects model was used to calculate the pooled OR [47], whereas the fixed effects model was used in its absence [48]. A sensitivity analysis was conducted to assess the stability of the results. For the control group of each study, the observed genotype frequency was assessed for HWE using the Pearson chi-square test; P<0.05 was considered significant. Funnel plots and Egger’s linear regression test were used to evaluate publication bias [49].

All statistical analyses were performed by using STATA (version 11.0; Stata Corporation, College Station, TX).

Results

Study Characteristics

Publications were retrieved based on the search criteria. Study selection process was shown in Figure 1. Among them, the distribution of GSTP1 genotypes in controls was not consistent with HWE for the GSTP1 polymorphism in 2 studies [44], [50]. In the study by Agalliu et al [18], the distribution of GSTP1 genotypes among controls was not in agreement with the HWE among Africans. These studies were excluded from the meta-analysis. Finally, a total of 28 case-control studies involving 6,790 cases and 7,375 controls were included. The characteristics of these studies are summarized in Table S1. There were 8 studies on subjects of Asian, 17 of Caucasian, 2 of African, and 1 of mixed ethnicity. Prostate cancer was confirmed histologically or pathologically in all studies. Detailed information about prostate cancer stage and grade (Gleason scores) were shown in seven studies [20], [21], [24], [26], [27], [33], [39]. The data on smoking status and GSTM1 null/present genotypes was available in four studies [25], [30], [42], [43].

[Figure omitted. See PDF.]

Figure 1. Flow chart of study selection based on the inclusion and exclusion criteria.

https://doi.org/10.1371/journal.pone.0071640.g001

Quantitative Synthesis

GSTP1 105Val allele frequencies in the cases and controls were calculated. The frequency of the 105Val allele was 30.12% (95%CI = 26.87–33.38%) in the cases, which was not significantly higher than that controls (29.17%; 95%CI = 26.02–32.33%, P = 0.67).

We performed a meta-analysis of the GSTP1 Ile105Val polymorphism overall, and in subgroups of ethnicities, clinical stage, and grade (Gleason scores) under various genetic models (Table S2). Overall, we did not find a significant association of Ile105Val polymorphism with the risk of prostate cancer (Val/Val vs. Ile/Ile: OR = 1.06, 95% CI = 0.90–1.25, P = 0.50; Val/Ile vs. Ile/Ile: OR = 1.02, 95% CI = 0.89–1.16, P = 0.83; Val/Val+Val/Ile vs. Ile/Ile: OR = 1.03, 95% CI = 0.91–1.16, P = 0.63; Val/Val vs. Val/Ile+Ile/Ile: OR = 1.07, 95% CI = 0.91–1.25, P = 0.44; Table S2, Figure 2). However, significant association of Ile105Val polymorphism was identified with low-stage prostate cancer (Val/Val vs. Ile/Ile: OR = 2.70, 95% CI = 1.73–4.22, P<0.001; Val/Val vs. Val/Ile+Ile/Ile: OR = 2.14, 95% CI = 1.38–3.33, P = 0.001; Table S2), but not with high-stage (Val/Val vs. Ile/Ile: OR = 1.57, 95% CI = 0.76–3.23, P = 0.22; Val/Val vs. Val/Ile+Ile/Ile: OR = 1.40 95% CI = 0.69–2.85, P = 0.35; Table S2). In addition, there was no evidence supporting that the Ile105Val polymorphism was significantly associated with prostate cancer risk in patients with high- and low-grade cancer (Table S2).

[Figure omitted. See PDF.]

Figure 2. Forest plot of prostate cancer risk associated with GSTP1 Ile105Val polymorphism (for Val/Val vs. Ile/Ile).

The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI.

https://doi.org/10.1371/journal.pone.0071640.g002

In subgroup analyses by ethnicities, the Ile105Val polymorphism was not associated with prostate cancer risk in Caucasians and Asians (Table S2).

Cumulative Meta-analysis

In this study, a cumulative meta-analysis was also performed, in which the studies were added one at a time according to year of publication. We found that the pooled ORs did not change according to year of publication (data not shown).

GSTP1- GSTM1 and GSTP1-smoking Interactions

The gene-gene and gene-environment interactions were assessed in our analysis. GSTM1 null/present genotypes have been identified [10], [51]. When the data were analyzed in subgroups of subjects stratified by GSTM1 null/present genotypes, we found that the Ile105Val polymorphism was not significantly associated with prostate cancer risk among patients with GSTM1 null genotype (Val/Val+Val/Ile vs. Ile/Ile: OR = 1.11 95% CI = 0.75–1.65, P = 0.56; Table S2), and among patients with GSTM1 present genotype (Table S2).

When the data were analyzed in subgroups of subjects stratified by smoking status, we did not find that GSTP1 Ile105Val polymorphism was significantly associated with prostate cancer risk among smokers (Val/Val+Val/Ile vs. Ile/Ile: OR = 0.90, 95% CI = 0.68–1.18, P = 0.43; Table S2), and among non-smokers (Table S2). The results were confirmed by logistic regression analysis and multifactor dimensionality reduction (MDR) method (data not shown).

Test of Heterogeneity

The heterogeneity was reckoned between each of the studies using the Q-test. Overall, the significant heterogeneity was detected (Val/Val vs. Ile/Ile: Pheterogeneity = 0.06; Val/Ile vs. Ile/Ile: Pheterogeneity <0.01; Val/Val+Val/Ile vs. Ile/Ile: Pheterogeneity <0.01; Val/Val vs. Val/Ile+Ile/Ile: Pheterogeneity = 0.08). In stratified analyses by clinical stage, significant heterogeneity was observed for low-stage prostate cancer under one genetic model (Val/Ile vs. Ile/Ile: Pheterogeneity = 0.001). In stratified analyses by smoking status and GSTM1 null/present genotypes, there was no evidence of heterogeneity.

Sensitivity Analysis

In the sensitivity analysis, the influence of each study on the pooled OR was examined by repeating the meta-analysis while omitting each study, one at a time. This procedure confirmed the stability of the overall result (data not shown).

Publication Bias

Begg’s funnel plot and Egger’s test were conducted to assess publication bias. The shape of funnel plots did not show any evidences of asymmetry. The Egger’s test did not provide any statistical evidence of funnel plot symmetry (Val/Val vs. Ile/Ile: P = 0.82; Val/Ile vs. Ile/Ile: P = 0.69; Val/Val+Val/Ile vs. Ile/Ile: P = 0.98; Val/Val vs. Val/Ile+Ile/Ile: P = 0.90, Figure 3).

[Figure omitted. See PDF.]

Figure 3. Begg’s funnel plots for publication bias test on studies assessing GSTP1 Ile105Val polymorphism and prostate cancer risk (A, Val/Val vs. Ile/Ile; B, Val/Ile vs. Ile/Ile; C, Val/Val vs. Val/Ile+Ile/Ile; D, Val/Val+Val/Ile vs. Ile/Ile).

Each circle represents as an independent study for the indicated association.

https://doi.org/10.1371/journal.pone.0071640.g003

Discussion

The present meta-analysis, including 6,790 prostate cancer cases and 7,375 controls, explored the association of one potentially functional polymorphism in the GSTP1 gene and prostate cancer risk. Overall, the significant association of GSTP1 Ile105Val polymorphism with prostate cancer risk was not detected. Moreover, the association was not significant in the subgroups according to ethnicity and prostate cancer grade. Reactive oxygen species generated from cigarette smoke are commonly thought to induce the formation of modified bases and single-strand breaks [52]–[54]. Accumulation of mutations in critical oncogenes and tumour suppressor genes promotes cancer. However, the results in our study does not support that smoking modifies the effect of GSTP1 Ile105Val polymorphism on prostate cancer risk. It is likely that GSTP1 enzyme activity in prostate cancer tissues has been reduced. The activity reduction may be due to hypermethylation of the CG island in the promoter region of the GSTP1 gene. Hence, it is speculated that the enzymatic differences due to the Ile105Val polymorphism might be not enough to affect overall prostate carcinogenesis and the roles of smoking. In addition, the influence of the genetic variant may be masked by the presence of other as-yet unidentified causal genes involved in prostate cancer. Further studies are warranted to define the etiology of this phenomenon.

Meta-analysis is a useful strategy for elucidating genetic factors in prostate cancer [55], [56]. GSTP1, which is involved in the detoxification of carcinogenic polycyclic aromatic hydrocarbons, has been investigated extensively in relation to different types of cancer, such as breast cancer [57], [58], bladder cancer [59], [60], oesophageal cancer [61], [62], and so on [5]. Previous results of the studies on the association of GSTP1 Ile105Val polymorphism with prostate cancer risk were inconclusive. These inconsistent results may be due to a small effect of the Ile105Val polymorphism on prostate cancer risk or the relatively low statistical power of the published studies. Although a meta-analysis has been published [63], the conclusion in our updated meta-analysis might be more convincing. In the meta-analysis [63], only 13 articles was included. However, in our meta-analysis, a total of 28 eligible studies were included which might lead to more convincing conclusions. In addition, gene-gene and gene-environment interactions were also investigated in our meta-analysis. Hence, we performed a meta-analysis for combining the results of various studies, and explaining their diversity. The results in the meta-analysis were more convincing.

In the meta-analysis, we did not find the significant association of Ile105Val polymorphism with overall prostate cancer risk. In the meta-analysis by Zhao et al [64], little evidence was found for the association between GSTP1 Ile105Val polymorphism and hepatocellular carcinoma risk. In another meta-analysis by Lang et al [65], the significant association between the GSTP1 Ile105Val polymorphism and the risk of head and neck cancers was not detected. In addition, the insignificant association of the Ile105Val polymorphism with thyroid cancer was also found in the meta-analysis by Li et al [66]. Hence, the overall conclusion in our study was consistent with that in other studies. However, we identified that the Ile105Val polymorphism was significantly associated with low-stage prostate cancer. This result suggested that enzymatic differences due to different GSTP1 genotypes played a pivotal role, and might influence the early phases of prostate cancer. The role of GSTP1 Ile105Val polymorphism might be specific according to low or high-stage of prostate cancer. Given the important functions of GSTP1 gene, it is biologically plausible that GSTP1 Ile105Val polymorphism may modify the risk of low-stage prostate cancer. Further experiments are needed to elucidate the difference.

GSTP1 was thought to be involved in detoxification of epoxides from carcinogenic polycyclic aromatic hydrocarbons and combination of exposure to cigarette smoking. Lack of GSTP1 activity might increase the burden with ultimate carcinogenic epoxides. In the stratified analyses by smoking status, the significant relationships were neither found among non-smokers nor smokers. It suggested that smoking might not significantly modify the effect of GSTP1 polymorphism on the risk of prostate cancer. However, the results on undetected effects should be interpreted with caution because of a relatively small sample size included in the subgroup.

Several limitations should be addressed in the meta-analysis. First, limited data restricted our further evaluation of potential GSTP1-GSTT1 interaction. Second, the sample size on the African populations was relatively small. Third, our results were based on the unadjusted evaluation. In order to provide a more precise estimation on the basis of adjustment for the confounders, well designed studies taking the potential confounders such as age into account are warranted. Forth, limited data in prospective case-control studies were included.

In summary, this meta-analysis provided evidence that the Ile105Val polymorphism was not related to overall prostate cancer risk. In subgroup analyses, the significant association of GSTP1 105Val allele with low-stage prostate cancer risk was observed. However, more sophisticated GSTP1–GSTT1 interaction should be considered for future experimental design, which would allow a comprehensive understanding of the association between GSTP1 Ile105Val and prostate cancer risk.

Supporting Information

[Figure omitted. See PDF.]

Table S1.

Characteristics of studies included in the meta-analysis.

https://doi.org/10.1371/journal.pone.0071640.s001

(DOC)

Table S2.

Stratified analyses of the GSTP1 Ile105Val polymorphism on prostate cancer risk.

https://doi.org/10.1371/journal.pone.0071640.s002

(DOC)

Author Contributions

Conceived and designed the experiments: BW ZX. Performed the experiments: BW ZX JR MZ. Analyzed the data: BW JR MZ. Contributed reagents/materials/analysis tools: All authors. Wrote the paper: BW ZX.

Citation: Wei B, Zhou Y, Xu Z, Ruan J, Cheng H, Zhu M, et al. (2013) GSTP1 Ile105Val Polymorphism and Prostate Cancer Risk: Evidence from a Meta-Analysis. PLoS ONE 8(8): e71640. https://doi.org/10.1371/journal.pone.0071640

References

1. Gronberg H (2003) Prostate cancer epidemiology. Lancet 361: 859–64.

2. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61: 212–36.

3. Dunn MW, Kazer MW (2011) Prostate cancer overview. Semin Oncol Nurs 27: 241–50.

4. Latil AG, Azzouzi R, Cancel GS, Guillaume EC, Cochan-Priollet B, et al. (2001) Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Cancer 92: 1130–7.

5. Di Pietro G, Magno LA, Rios-Santos F (2010) Glutathione S-transferases: an overview in cancer research. Expert Opin Drug Metab Toxicol 6: 153–70.

6. Rebbeck TR (1997) Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev 6: 733–43.

7. Hayes JD, Strange RC (2000) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61: 154–66.

8. Di Ilio C, Aceto A, Bucciarelli T, Angelucci S, Felaco M, et al. (1990) Glutathione transferase isoenzymes from human prostate. Biochem J 271: 481–5.

9. Tsuchida S, Sato K (1992) Glutathione transferases and cancer. Crit Rev Biochem Mol Biol 27: 337–84.

10. Katoh T, Yamano Y, Tsuji M, Watanabe M (2008) Genetic polymorphisms of human cytosol glutathione S-transferases and prostate cancer. Pharmacogenomics 9: 93–104.

11. Ntais C, Polycarpou A, Ioannidis JP (2005) Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 14: 176–81.

12. De Marzo AM, Marchi VL, Epstein JI, Nelson WG (1999) Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 155: 1985–92.

13. Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, et al. (1994) Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci U S A 91: 11733–7.

14. Cookson MS, Reuter VE, Linkov I, Fair WR (1997) Glutathione S-transferase PI (GST-pi) class expression by immunohistochemistry in benign and malignant prostate tissue. J Urol 157: 673–6.

15. Moskaluk CA, Duray PH, Cowan KH, Linehan M, Merino MJ (1997) Immunohistochemical expression of pi-class glutathione S-transferase is down-regulated in adenocarcinoma of the prostate. Cancer 79: 1595–9.

16. Johansson AS, Stenberg G, Widersten M, Mannervik B (1998) Structure-activity relationships and thermal stability of human glutathione transferase P1–1 governed by the H-site residue 105. J Mol Biol 278: 687–98.

17. Lavender NA, Benford ML, VanCleave TT, Brock GN, Kittles RA, et al. (2009) Examination of polymorphic glutathione S-transferase (GST) genes, tobacco smoking and prostate cancer risk among men of African descent: a case-control study. BMC Cancer 9: 397.

18. Agalliu I, Langeberg WJ, Lampe JW, Salinas CA, Stanford JL (2006) Glutathione S-transferase M1, T1, and P1 polymorphisms and prostate cancer risk in middle-aged men. Prostate 66: 146–56.

19. Rybicki BA, Neslund-Dudas C, Nock NL, Schultz LR, Eklund L, et al. (2006) Prostate cancer risk from occupational exposure to polycyclic aromatic hydrocarbons interacting with the GSTP1 Ile105Val polymorphism. Cancer Detect Prev 30: 412–22.

20. Xu X, Chang W, Hou J, Xu D, Cui X, et al. (2010) Relationship of GSTP1,RASSF1A polymorphisms and environmental agent with susceptibility to prostate cancer:a case-control study. Academic Journal of Second Military Medical University 31: 12–7.

21. Wang G, Jiang J, Jin F, Wang L, Wan J (2008) Polymorphisms of glutathione-S-transferase gene Pi (GSTP1) and prostate cancer risk in Chinese population. Shanxi Med J 37: 410–2.

22. Srivastava DS, Mandhani A, Mittal B, Mittal RD (2005) Genetic polymorphism of glutathione S-transferase genes (GSTM1, GSTT1 and GSTP1) and susceptibility to prostate cancer in Northern India. BJU Int 95: 170–3.

23. Qadri Q, Sameer AS, Shah ZA, Hamid A, Alam S, et al. (2011) Genetic polymorphism of the glutathione-S-transferase P1 gene (GSTP1) and susceptibility to prostate cancer in the Kashmiri population. Genet Mol Res 10: 3038–45.

24. Vijayalakshmi K, Vettriselvi V, Krishnan M, Shroff S, Vishwanathan KN, et al. (2005) Polymorphisms at GSTM1 and GSTP1 gene loci and risk of prostate cancer in a South Indian population. Asian Pac J Cancer Prev 6: 309–14.

25. Komiya Y, Tsukino H, Nakao H, Kuroda Y, Imai H, et al. (2005) Human glutathione S-transferase A1, T1, M1, and P1 polymorphisms and susceptibility to prostate cancer in the Japanese population. J Cancer Res Clin Oncol 131: 238–42.

26. Nakazato H, Suzuki K, Matsui H, Koike H, Okugi H, et al. (2003) Association of genetic polymorphisms of glutathione-S-transferase genes (GSTM1, GSTT1 and GSTP1) with familial prostate cancer risk in a Japanese population. Anticancer Res 23: 2897–902.

27. Kwon DD, Lee WJ, Han YD, Seo Y, Park CS, et al. (2011) Relationship between the Glutathione-S-Transferase P1, M1, and T1 Genotypes and Prostate Cancer Risk in Korean Subjects. Korean J Urol 52: 247–52.

28. Gsur A, Haidinger G, Hinteregger S, Bernhofer G, Schatzl G, et al. (2001) Polymorphisms of glutathione-S-transferase genes (GSTP1, GSTM1 and GSTT1) and prostate-cancer risk. Int J Cancer 95: 152–5.

29. Nam RK, Zhang WW, Trachtenberg J, Jewett MA, Emami M, et al. (2003) Comprehensive assessment of candidate genes and serological markers for the detection of prostate cancer. Cancer Epidemiol Biomarkers Prev 12: 1429–37.

30. Autrup JL, Thomassen LH, Olsen JH, Wolf H, Autrup H (1999) Glutathione S-transferases as risk factors in prostate cancer. Eur J Cancer Prev 8: 525–32.

31. Steinhoff C, Franke KH, Golka K, Thier R, Romer HC, et al. (2000) Glutathione transferase isozyme genotypes in patients with prostate and bladder carcinoma. Arch Toxicol 74: 521–6.

32. Ashtiani ZO, Hasheminasab SM, Ayati M, Goulian BS, Modarressi MH (2011) Are GSTM1, GSTT1 and CAG repeat length of androgen receptor gene polymorphisms associated with risk of prostate cancer in Iranian patients? Pathol Oncol Res 17: 269–75.

33. Antognelli C, Mearini L, Talesa VN, Giannantoni A, Mearini E (2005) Association of CYP17, GSTP1, and PON1 polymorphisms with the risk of prostate cancer. Prostate 63: 240–51.

34. Jeronimo C, Varzim G, Henrique R, Oliveira J, Bento MJ, et al. (2002) I105V polymorphism and promoter methylation of the GSTP1 gene in prostate adenocarcinoma. Cancer Epidemiol Biomarkers Prev 11: 445–50.

35. Wadelius M, Autrup JL, Stubbins MJ, Andersson SO, Johansson JE, et al. (1999) Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and their association with prostate cancer. Pharmacogenetics 9: 333–40.

36. Kote-Jarai Z, Easton D, Edwards SM, Jefferies S, Durocher F, et al. (2001) Relationship between glutathione S-transferase M1, P1 and T1 polymorphisms and early onset prostate cancer. Pharmacogenetics 11: 325–30.

37. Nock NL, Liu X, Cicek MS, Li L, Macarie F, et al. (2006) Polymorphisms in polycyclic aromatic hydrocarbon metabolism and conjugation genes, interactions with smoking and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 15: 756–61.

38. Beer TM, Evans AJ, Hough KM, Lowe BA, McWilliams JE, et al. (2002) Polymorphisms of GSTP1 and related genes and prostate cancer risk. Prostate Cancer Prostatic Dis 5: 22–7.

39. Kidd LC, Woodson K, Taylor PR, Albanes D, Virtamo J, et al. (2003) Polymorphisms in glutathione-S-transferase genes (GST-M1, GST-T1 and GST-P1) and susceptibility to prostate cancer among male smokers of the ATBC cancer prevention study. Eur J Cancer Prev 12: 317–20.

40. Shepard TF, Platz EA, Kantoff PW, Nelson WG, Isaacs WB, et al. (2000) No association between the I105V polymorphism of the glutathione S-transferase P1 gene (GSTP1) and prostate cancer risk: a prospective study. Cancer Epidemiol Biomarkers Prev 9: 1267–8.

41. Debes JD, Yokomizo A, McDonnell SK, Hebbring SJ, Christensen GB, et al. (2004) Gluthatione-S-transferase P1 polymorphism I105V in familial and sporadic prostate cancer. Cancer Genet Cytogenet 155: 82–6.

42. Lima MM Jr, Oliveira MN, Granja F, Trindade AC, De Castro Santos LE, et al. (2008) Lack of association of GSTT1, GSTM1, GSTO1, GSTP1 and CYP1A1 polymorphisms for susceptibility and outcome in Brazilian prostate cancer patients. Folia Biol (Praha) 54: 102–8.

43. Mao GE, Morris G, Lu QY, Cao W, Reuter VE, et al. (2004) Glutathione S-transferase P1 Ile105Val polymorphism, cigarette smoking and prostate cancer. Cancer Detect Prev 28: 368–74.

44. Safarinejad MR, Shafiei N, Safarinejad SH (2011) Glutathione S-transferase gene polymorphisms (GSTM1, GSTT1, GSTP1) and prostate cancer: a case-control study in Tehran, Iran. Prostate Cancer Prostatic Dis 14: 105–13.

45. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127: 820–6.

46. Berman NG, Parker RA (2002) Meta-analysis: neither quick nor easy. BMC Med Res Methodol 2: 10.

47. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719–48.

48. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–88.

49. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–34.

50. Sivonova M, Waczulikova I, Dobrota D, Matakova T, Hatok J, et al. (2009) Polymorphisms of glutathione-S-transferase M1, T1, P1 and the risk of prostate cancer: a case-control study. J Exp Clin Cancer Res 28: 32.

51. Lai MT, Chen RH, Tsai FJ, Wan L, Chen WC (2005) Glutathione S-transferase M1 gene but not insulin-like growth factor-2 gene or epidermal growth factor gene is associated with prostate cancer. Urol Oncol 23: 225–9.

52. Nakayama T, Kaneko M, Kodama M, Nagata C (1985) Cigarette smoke induces DNA single-strand breaks in human cells. Nature 314: 462–4.

53. Winston GW, Church DF, Cueto R, Pryor WA (1993) Oxygen consumption and oxyradical production from microsomal reduction of aqueous extracts of cigarette tar. Arch Biochem Biophys 304: 371–8.

54. Leanderson P, Tagesson C (1994) Cigarette tar promotes neutrophil-induced DNA damage in cultured lung cells. Environ Res 64: 103–11.

55. Wei B, Xu Z, Ruan J, Zhu M, Jin K, et al. (2012) RNASEL Asp541Glu and Arg462Gln polymorphisms in prostate cancer risk: evidences from a meta-analysis. Mol Biol Rep 39: 2347–53.

56. Wei B, Zhou Y, Xu Z, Ruan J, Zhu M, et al. (2011) XRCC1 Arg399Gln and Arg194Trp polymorphisms in prostate cancer risk: a meta-analysis. Prostate Cancer Prostatic Dis 14: 225–31.

57. Pongtheerat T, Pakdeethai S, Purisa W, Chariyalertsak S, Petmitr S (2011) Promoter methylation and genetic polymorphism of glutathione S-transferase P1 gene (GSTP1) in Thai breast- cancer patients. Asian Pac J Cancer Prev 12: 2731–4.

58. Lee SA, Fowke JH, Lu W, Ye C, Zheng Y, et al. (2008) Cruciferous vegetables, the GSTP1 Ile105Val genetic polymorphism, and breast cancer risk. Am J Clin Nutr 87: 753–60.

59. Safarinejad MR, Safarinejad S, Shafiei N (2011) Association of genetic polymorphism of glutathione S-transferase (GSTM1, GSTT1, GSTP1) with bladder cancer susceptibility. Urol Oncol.

60. Yokomizo A, Yamamoto K, Kinukawa N, Tsunoda T, Koga H, et al. (2007) Association analysis of glutathione-S-transferase P1 (GSTP1) polymorphism with urothelial cancer susceptibility and myelosuppression after M-VAC chemotherapy. Int J Urol 14: 500–4.

61. Li D, Dandara C, Parker MI (2010) The 341C/T polymorphism in the GSTP1 gene is associated with increased risk of oesophageal cancer. BMC Genet 11: 47.

62. Sameer AS, Qadri Q, Siddiqi MA (2012) GSTP1 I105V polymorphism and susceptibility to colorectal cancer in Kashmiri population. DNA Cell Biol 31: 74–9.

63. Yu Z, Li Z, Cai B, Wang Z, Gan W, et al. (2013) Association between the GSTP1 Ile105Val polymorphism and prostate cancer risk: a systematic review and meta-analysis. Tumour Biol 34: 1855–63.

64. Zhao Y, Wang Q, Deng X, Shi P, Wang Z (2013) Quantitative assessment of the association between GSTP1 gene Ile105Val polymorphism and susceptibility to hepatocellular carcinoma. Tumour Biol.

65. Lang J, Song X, Cheng J, Zhao S, Fan J (2012) Association of GSTP1 Ile105Val polymorphism and risk of head and neck cancers: a meta-analysis of 28 case-control studies. PLoS One 7: e48132.

66. Li J, Long J, Hu Y, Tan A, Guo X, et al. (2012) Glutathione S-transferase M1, T1, and P1 polymorphisms and thyroid cancer risk: a meta-analysis. Cancer Epidemiol 36: e333–40.