Skip to main content
NCBI home page
PLOS Medicine logoLink to PLOS Medicine
. 2006 Mar 7;3(4):e91. doi: 10.1371/journal.pmed.0030091

Five Glutathione S-Transferase Gene Variants in 23,452 Cases of Lung Cancer and 30,397 Controls: Meta-Analysis of 130 Studies

Zheng Ye 1,*, Honglin Song 2, Julian P T Higgins 3, Paul Pharoah 1,2, John Danesh 1
Editor: Cathryn Lewis4
PMCID: PMC1391981  PMID: 16509765

Abstract

Background

Glutathione S-transferases (GSTs) are known to abolish or reduce the activities of intracellular enzymes that help detoxify environmental carcinogens, such as those found in tobacco smoke. It has been suggested that polymorphisms in the GST genes are risk factors for lung cancer, but a large number of studies have reported apparently conflicting results.

Methods and Findings

Literature-based meta-analysis was supplemented by tabular data from investigators of all relevant studies of five GST polymorphisms ( GSTM1 null, GSTT1 null, I105V, and A114V polymorphisms in the GSTP1 genes, and GSTM3 intron 6 polymorphism) available before August, 2005, with investigation of potential sources of heterogeneity. Included in the present meta-analysis were 130 studies, involving a total of 23,452 lung cancer cases and 30,397 controls. In a combined analysis, the relative risks for lung cancer of the GSTM1 null and GSTT1 null polymorphisms were 1.18 (95% confidence interval [CI]: 1.14–1.23) and 1.09 (95% CI: 1.02–1.16), respectively, but in the larger studies they were only 1.04 (95% CI: 0.95–1.14) and 0.99 (95% CI: 0.86–1.11), respectively. In addition to size of study, ethnic background was a significant source of heterogeneity among studies of the GSTM1 null genotype, with possibly weaker associations in studies of individuals of European continental ancestry. Combined analyses of studies of the 105V, 114V, and GSTM3*B variants showed no significant overall associations with lung cancer, yielding per-allele relative risks of 1.04 (95% CI: 0.99–1.09), 1.15 (95% CI: 0.95–1.39), and 1.05 (95% CI: 0.89–1.23), respectively.

Conclusions

The risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with GSTM3 intron 6 polymorphism. Given the non-significant associations in the larger studies, the relevance of the weakly positive overall associations with the GSTM1 null and the GSTT1 null polymorphisms is uncertain. As lung cancer has important environmental causes, understanding any genetic contribution to it in general populations will require the conduct of particularly large and comprehensive studies.

Large meta-analysis finds little evidence for a link between gene variants encoding inactive or less active variants of detoxifying enzymes and lung cancer risk.

Introduction

Glutathione S-transferases (GSTs, Enzyme Commission 2.5.1.18) are a large family of cytosolic enzymes that catalyze the detoxification of reactive electrophilic compounds, including many environmental carcinogens (e.g., benzo[a]pyrene and other polycyclic aromatic hydrocarbons) [ 1, 2]. Inter-individual variability in GST enzyme activity is believed to confer differences in susceptibility to cancers with major environmental determinants such as lung cancer [ 3, 4, 5]. Some genetic variants in the glutathione S-transferase genes, such as the GSTM1 null polymorphism, are known to abolish enzyme activities ( Table 1). Because individuals with the GSTM1 null genotype have been reported to have higher levels of polycyclic aromatic hydrocarbon-dGMP adducts (which can induce genetic mutations) in lung tissue than those with the GSTM1 genotype [ 4], such genetic variants have been extensively studied as candidates for lung cancer susceptibility, but studies have yielded apparently conflicting results [ 6– 142]. This may be due, in part, to involvement of only a few hundred cases and a few hundred controls in most studies, too few to assess reliably any moderate genetic effects in lung cancer. The interpretation of these studies has been further complicated by studies involving: (i) different GST polymorphisms, (ii) populations with different background smoking patterns and with different ethnic compositions (e.g., European and African populations have substantially different frequencies of certain GST genetic variants), and (iii) different control groups (e.g., population versus hospital based).

Table 1. Description of Glutathione S-Transferase Polymorphisms.

graphic file with name pmed.0030091.t001.jpg

Open in a new tab

Five common variants in four GST genes ( GSTM1, GSTT1, GSTP1, and GSTM3, described in Table 1) have been studied extensively in relation to lung cancer, with each associated with completely lost or reduced activities of certain xenobiotic metabolizing enzymes: (i) the GSTM1*0 ( GSTM1 null), (ii) the GSTT1*0 ( GSTT1 null) alleles represent deletions of the GSTM1 and GSTT1 genes, respectively, with each conferring a total loss of activity in their corresponding enzymes [ 5], (iii) the A to G transition in GSTP1 that gives rise to the Ile105Val polymorphism (also known as I105V), (iv) the C to T exchange at position 341 in the same gene, which results in the Ala114Val polymorphism (also known as A114V) (both of these GSTP1 polymorphisms confer moderately reduced enzyme activity) [ 143], and (v) the GSTM3 intron 6 polymorphism, a 3-base pair deletion in intron 6, which is in linkage disequilibrium with the GSTM1 genotype and contains a recognition motif for the YY1 transcription factor, which has been postulated to regulate gene expression [ 144– 146].

The present report provides a meta-analysis of published genetic association studies, supplemented by tabular data received from study investigators of these five GST variants and risk of lung cancer. It includes an updated meta-analysis of 119 association studies of the GSTM1 null polymorphism and lung cancer (involving a total of 19,729 cancer cases and 25,931 controls, about three times as many participants as in previous such reviews [ 147– 149]), as well as completely new syntheses of four other GST polymorphisms (i.e., the GSTT1 null polymorphism, I105V, and A114V polymorphisms in the GSTP1 gene, and the GSTM3 intron 6 polymorphism). Hence, in aggregate, the present meta-analysis involves a total of 23,452 cancer cases and 30,397 controls in 130 studies (with the cases and controls in each study counted only once).

Methods

Data Searching

Genetic association studies published before August, 2005, investigating at least one of the five polymorphisms in the GST genes described above and lung cancer risk were sought by computer-based searches, scanning of the reference lists for all relevant studies and review articles (including meta-analyses), hand searching of relevant journals, and correspondence with authors of included studies. Computer searches of PubMed, Web of Science, EMBASE, and CNKI ( http://www.cnki.net) used keywords relating to the relevant genes (e.g., “GSTT1,” “GSTP1,” “GSTM3,” and “glutathione S-transferase”) in combination with words related to lung cancer or lung-neoplasms without language restriction. All relevant studies identified were included apart from one study in which genotype frequencies were unavailable [ 120]. Twenty-two reports involved overlapping or duplicated data with studies already included in the present review [ 121– 142].

Data Abstraction

The following information was abstracted from each study according to a fixed protocol: study design, geographical location, ethnic group of participants, definition and numbers of cases and controls, DNA extraction and genotyping methods, frequency of genotypes, mean age of lung cancer cases, and proportion of lung cancer cases who were male ( Table S1). Previously un-reported data were included from four of these studies following correspondence that sought genotype frequencies on polymorphisms described in this review that were not reported in the original publications. In the few instances in which genotype frequencies provided by the investigators in tabular data differed slightly from published figures, the tabular data were used. Studies with different ethnic groups, and different source of controls were considered as individual studies for our analyses [ 6, 9, 10, 17, 23, 27, 41, 55].

Statistical Methods

The per-allele odds ratio (“relative risk”) of the rare allele (105V, 114V, GSTM3*B) was compared between cases and controls by assigning scores of 0, 1, and 2 to common homozygote, heterozygote, and rare homozygote, respectively, and calculating odds ratios per unit score by logistic regression; this is analogous to modeling a co-dominant model of inheritance. Subsidiary analyses involved dominant and recessive genetic models, where possible. For GSTM1 and GSTT1 status with only two possible genotypes, the odds ratio was compared between cases and controls by the Mantel-Haenszel method. To make some allowance for multiple comparisons, 99% confidence intervals (CI) were used for individual studies, and 95% CI were reserved for the combined estimates. Random-effects and fixed-effect summary measures were calculated as inverse-variance weighted average of the log odds ratios. Heterogeneity was assessed using the I 2 statistic, which describes the proportion of variation in the log odds ratios that is attributable to genuine differences across studies rather than to random error [ 150], and by the χ 2 test [ 151]. The among-study variance (τ 2) was used to quantify the degree of heterogeneity among studies [ 152]. Percentage of τ 2 explained is used to describe the extent to which study-level characteristics (e.g., sample size, sources of controls) explain heterogeneity, whereas the χ 2 test for interaction compares meta-analyses performed within types of participants (e.g., cancer type, smoking status). Subsidiary analyses involved subgroup analyses or random-effects meta-regression. Publication bias was assessed using funnel plots (so-called because, in the absence of publication bias, such plots resemble symmetrical inverted funnels), Begg's test [ 153] and the Trim and Fill method [ 154], which estimates the number and outcomes of potentially missing studies due to publication bias. Study size ( ≥ 500 cases, 200–499 cases, and < 200 cases), source of controls (e.g., population versus hospital based), ethnicity (individuals of European continental ancestry, East Asian, and other), and cancer type (squamous, adenocarcinoma, small cell carcinoma, and other) were pre-specified as characteristics for assessment of heterogeneity; other potentially relevant subgroup analyses (such as age, sex, and smoking status) could not reliably be investigated because individual participant data were not available in this meta-analysis. Statistical analyses were done using Stata (version 8.0) statistical software (Stata Corporation, College Station, Texas, United States). Because data on the joint occurrence of genetic variants (such as the I105V and A114V polymorphisms) have generally not been reported in published studies, analyses of such haplotypes (i.e., combination of alleles at multiple positions along a genomic segment of a single chromosome) cannot be provided in this review. In the figures, areas of squares of individual studies (or sets of studies) are inversely proportional to the variances of the log odds ratios, and the horizontal lines represent CIs. Studies in the figures are listed in descending order of statistical weight.

Results

A total of 130 relevant genetic association studies (126 published and four unpublished) were identified, with 48 studies genotyping more than one variant ( Table S1). For the GSTM1 null polymorphism, 119 studies involved a total of 19,729 cases and 25,931 controls (weighted mean age of cases 63 years; 55% male). For the GSTT1 null polymorphism, 44 studies involved a total of 9,636 cases and 12,322 controls (weighted mean age of cases 61 years; 59% male). For the GSTP1 I105V polymorphism, 25 studies involved a total of 6,221 cases and 7,602 controls (weighted mean age of cases 64 years; 68% male) and for the A114V polymorphism of the same gene, four studies involved a total of 1,251 cases and 1,295 controls (weighted mean age of cases 61 years; 52% male) [ 29, 77, 92, 95]. For GSTM3 intron 6 polymorphism, five studies involved a total of 1,238 cases and 1,179 controls (weighted mean age of cases 62 years; 85% male) [ 37, 70, 73, 78, 88].

Studies were conducted in a wide range of geographical settings, with 48% of lung cancer cases being individuals of European continental ancestry, 37% East Asian, and 15% of other ethnic origins (including African American, Turkish, and Mexican American) [ 8, 17, 22, 41, 64, 67]. Of the 130 studies, 124 were retrospective case-control studies and six were prospective in design (cohort or nested case-control) [ 32, 56, 61, 65, 78, 95]. Of the 124 retrospective studies, 80 involved controls drawn at random from approximately general populations (e.g., population registers), 25 involved controls from health-check visits or outpatient clinics, and 19 involved controls drawn from groups of patients free of cancer. Of the 124 retrospective studies, 20 matched controls to cases by age, and a further 26 matched controls to cases by age and at least one other risk factor. All but one study [ 99] used polymerase chain reaction/restriction fragment length polymorphism with various restriction enzymes to perform genotyping (the remaining study used oligonucleotide probes).

There was evidence of a moderate degree of heterogeneity among the 119 studies of the GSTM1 null genotype (I 2 = 44%, 95% CI: 30% to 55%, p < 0.0001). Study characteristics such as sample size (explaining 18% of τ 2, p < 0.0001), and ethnicity (44% of τ 2, p < 0.0001) explained much of the heterogeneity, whereas source of controls (0% of τ 2, p = 0.82) and cancer type (χ 2 3 = 1.49, p = 0.69) explained a relatively small fraction. Overall, the relative risk for lung cancer risk of the GSTM1 null genotype was 1.22 (95% CI: 1.16–1.30) using a random-effects model and 1.18 (95% CI: 1.14–1.23; Figures 1 and 2) using a fixed-effect model, but a funnel plot of these 119 studies suggested a possibility of the preferential publication of strikingly positive findings in smaller studies (Begg's test, p < 0.0001; Figure S1). Analysis restricted to the five studies with at least 500 cases (total of 3,436 cases and 3,897 controls), which should be less prone to selective publication than are the smaller studies, yielded a relative risk of 1.04 (95% CI: 0.95–1.14), which is not statistically significant. Further evidence of selective publication derives from the results of the Trim and Fill approach, which suggested that 28 missing studies are required to make the funnel plot symmetrical ( Figure S2).

Figure 1. Meta-Analyses of Studies of Lung Cancer and Five GST Gene Polymorphisms ( GSTM1 null, GSTT1 null, and GSTP1 I105V, GSTP1 A114V, and GSTM3 intron 6) Grouped by Various Characteristics .

Figure 1

Open in a new tab

Figure 2. Meta-Analysis of Studies of GSTM1 Polymorphism and Lung Cancer .

Figure 2

Open in a new tab

The horizontal axis is plotted on a log doubling scale.

There was a moderately high degree of heterogeneity among the 44 studies of the GSTT1 null genotype (I 2 = 57%, 95% CI: 40% to 70%, p < 0.0001). Study characteristics such as sample size (17% of τ 2 explained, p = 0.01) and ethnicity (31% of τ 2, p = 0.02) explained some of the heterogeneity, but source of controls (0% of τ 2, p = 0.02) and cancer type (χ 2 3 = 5.55, p = 0.14) did not explain much of it. Overall, the relative risk for lung cancer of the GSTT1 null genotype was 1.13 (95% CI: 1.02–1.26) using a random-effects model and 1.09 (95% CI: 1.02–1.16; Figures 1 and 3) using a fixed-effect model. A funnel plot did not indicate the presence of publication bias in these studies (Begg's test p = 0.14; plot available on request), and an analysis of the four studies with at least 500 cases (total of 2,767 cases and 3,110 controls) yielded a relative risk of 0.99 (95% CI: 0.86–1.11).

Figure 3. Meta-Analysis of Studies of GSTT1 Polymorphism and Lung Cancer .

Figure 3

Open in a new tab

The horizontal axis is plotted on a log doubling scale.

There was no significant heterogeneity among the 25 studies of the 105V variant in the GSTP1 gene and lung cancer (I 2 = 0% 95% CI: 0% to 44%, p = 0.66). Overall, the per-allele relative risk for lung cancer of the 105V variant was 1.04 (95% CI: 0.99–1.09; Figures 1 and 4), with corresponding results under dominant and recessive genetic models of 1.02 (95% CI: 0.95–1.09) and 1.13 (95% CI: 1.01–1.27), respectively. There was no significant heterogeneity among the four studies of the 114V variant of the same gene (I 2 = 0%, 95% CI: 0% to 85%, p = 0.39). The overall per-allele risk of the 114V variant for lung cancer was 1.15 (95% CI: 0.95–1.39), with corresponding results under dominant and recessive genetic models of 1.17 (95% CI: 0.95–1.45) and 1.27 (95% CI: 0.48–3.33; Figures 1 and 5), respectively. There was no significant heterogeneity among the five studies of the GSTM3*B variant (I 2 = 0%, 95% CI: 0% to 79%, p = 0.95). The overall per-allele risk of the GSTM3*B variant for lung cancer was 1.05 (95% CI: 0.89–1.23; Figures 1 and 6), with corresponding results under dominant and recessive genetic models of 1.11 (95% CI: 0.92–1.34) and 0.91 (95% CI: 0.52–1.57), respectively.

Figure 4. Meta-Analysis of Studies of GSTP1 I105V Polymorphism and Lung Cancer .

Figure 4

Open in a new tab

The horizontal axis is plotted on a log doubling scale.

Figure 5. Meta-Analysis of Studies of GSTP1 A114V and GSTM3 Intron 6 Polymorphisms and Lung Cancer .

Figure 5

Open in a new tab

The horizontal axis is plotted on a log doubling scale.

Discussion

The present meta-analysis of 130 genetic association studies involves more than 23,000 cases and 30,000 controls and provides the most comprehensive assessment so far of the relevance to lung cancer of five GST gene polymorphisms. This review indicates that the risk of lung cancer is not strongly associated with the I105V and A114V polymorphisms in the GSTP1 gene or with the GSTM3 intron 6 polymorphism. The relevance of the weakly positive overall associations observed of the GSTM1 null and of the GSTT1 null genotypes with the risk of lung cancer is uncertain, particularly given the non-significant relative risks observed for each variant in the larger studies (which should be less prone to selective reporting than are the smaller studies). At least for the studies of the GSTM1 null variant, there is a possibility that the magnitude of the association varies significantly by characteristics such as ethnic background.

The potential limitations of the present report merit consideration. Although the available data on three of the polymorphisms (i.e., GSTM1 null, GSTT1 null, and GSTP1 105V) comprise at least 6,000 cases and at least 7,000 controls for each of these variants, the present data on the GSTP1 114V and the GSTM3*B variants (comprising only about 1,000 cases and about 1,000 controls for each) are much sparser—too few to enable reliable assessments of any per-allele relative risks of about 10% to 20%. Even for the more extensively studied variants, moreover, the present data are insufficient to enable reliable assessment of the impact of the genotypes in potentially relevant subgroups, such as those defined by ethnic background or by cancer histology. Lack of individual data in the present review prevents more detailed analyses, such as any joint effects of gene-gene or gene-environment factors. Funnel plots suggest publication bias in studies of only one of the five variants considered (i.e., the GSTM1 null genotype), but it is difficult to exclude this bias in studies of the four other variants despite our attempts to identify un-reported data by correspondence with investigators and exploration of data for the possible effects of selective publication.

The pathways of carcinogen metabolism are complex, mediated by the activities of multiple genes (such as GSTM1, and CYP1A1 [ 3, 155]). The effect of any single gene might have more limited impact on lung cancer than has so far been anticipated. The failure to demonstrate important associations between each of the five GST polymorphisms and lung cancer does not necessarily exclude the possibility that other variants (or combinations of alleles at multiple positions) in the same genes could be materially relevant to lung cancer. A more comprehensive empirical approach, in which all common variants are identified by resequencing followed by the genotyping of a tagging set of variants, may prove productive [ 156, 157]. The examples in this review, therefore, illustrate the need for much larger and more comprehensive studies than have been customary in order to evaluate reliably any moderate genetic effects that might be realistically expected in a complex disease such as lung cancer, which has known major environmental determinants [ 158].

Supporting Information

Figure S1. Funnel Plot of Studies of GSTM1 Null Polymorphism and Lung Cancer Showing a Possible Excess of Smaller Studies with Strikingly Positive Findings beyond the 95% CI; Begg's Test, p < 0.0001 .

(52 KB PPT).

Click here for additional data file. (52.5KB, ppt)
Figure S2. Trimmed and Filled Funnel Plot of GSTM1 Null Polymorphism and Lung Cancer .

The hollow diamonds are the actual studies included in the meta-analysis, the squares are the Trimmed and Filled studies required to achieve symmetry.

(56 KB PPT).

Click here for additional data file. (56KB, ppt)
Table S1. Characteristics of Genetic Association Studies of Five GST Polymorphisms in the Present Meta-Analyses .

(670 KB DOC).

Click here for additional data file. (670KB, doc)

Accession Numbers

The UniGene ( http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unigene) accession numbers used in this paper are GSTM1 (Hs.301961), GSTM3 (Hs.2006), GSTP1 (Hs.523836), and GSTT1 (Hs.77490).

The GeneCard ( http://www.genecards.org) protein coding ID numbers are GSTM1 (GC01P109942), GSTM3 (GC019988), GSTP1 (GC11P067107), and GSTT1 (GC22M022700).

Patient Summary

Background

Genes and the environment determine a person's risk of cancer. For some cancers, strong environmental risk factors have been identified. One such example is lung cancer, where the large majority of cases are caused by smoking. However, some people who never smoke get lung cancer, and some heavy smokers do not. To help understand such cases, scientists have studied a group of genes called glutathione S-transferase genes. These genes contain the genetic information to make a group of proteins, the glutathione s-transferases, which detoxify environmental poisons such as those contained in cigarette smoke. Different people have slightly different versions of these genes. Some of these gene variants are thought to result in less active or even completely inactive proteins. Scientists have wondered whether these different gene variants influence the lung cancer risk in smokers and non-smokers. To find out, they have done a lot of studies, some small, some large, to test whether there are associations between particular glutathione s-transferase gene variants and the risk of lung cancer.

Why Was This Study Done?

Such association studies compare a group of people with lung cancer and a very similar group without lung cancer. Researchers determine the genetic make-up of both groups and ask whether a particular gene variant is more common among either the cancer patients (the “cases”) or the people without cancer (the “controls”). A variant that is more common among the cases might convey a risk, and one that is more common among the controls might convey some level of protection. The larger the studies are, and the more similar the cases and controls are, the better the chance to detect a “real” association. However, association studies are notoriously difficult to interpret, and most scientists agree that several independent studies are necessary before one can be reasonably sure that a particular gene variant conveys a risk or a protection. A rigorous way to summarize and integrate the results from several individual association studies is to do what is called a meta-analysis.

What Did the Researchers Do and What Did They Find?

These researchers did such a meta-analysis of 130 studies. Together, the studies tested possible associations between five relatively common variants in four glutathione s-transferase genes and the occurrence of lung cancer. All of the variants tested resulted in either less active or inactive versions of the proteins. Some of the individual studies had found associations between one or several of the variants and lung cancer (suggesting that they conveyed a risk), others had not. Altogether, the studies included data from over 23,000 lung cancer patients and 30,000 control individuals without lung cancer. After summarizing all of the results, it became clear that none of the five variants, not even the ones that resulted in inactive proteins, conveyed a clearly strong risk for lung cancer.

What Does This Mean?

A rigorous assessment of the results to date suggests that none of the five variants conveys a clearly strong risk for lung cancer in the general population. The gene variants included were some of the obvious ones to study, but there might be others that have a strong influence on an individual's risk to get lung cancer. It is also possible that some of these gene variants convey a stronger risk in some subgroups, for example, in particular ethnic groups that share a common genetic background. Additional studies that look specifically at the risk in particular subgroups would be needed to find out whether this is indeed the case. And much larger studies would be needed to determine reliably whether there are genes that convey a small or moderate risk for (or protection against) lung cancer.

Where Can I Find More Information Online?

The following pages provide information on lung cancer and cancer genetics.

Pages from the US National Cancer Institute:

http://www.cancer.gov/cancertopics/types/lung

http://www.cancer.gov/cancertopics/prevention-genetics-causes/genetics

MedlinePlus pages:

http://www.nlm.nih.gov/medlineplus/lungcancer.html

Cancer Research UK pages:

http://www.cancerhelp.org.uk/help/default.asp?page=2787

CancerIndex:

http://www.cancerindex.org/clinks2l.htm

Acknowledgments

Shengping Hu helped to obtain some of the Chinese reports. Nadeem Sarwar, Anna Bennet, and Stephen Kaptoge commented helpfully. The following investigators kindly provided additional information from their studies: Andy Povey, Adelin Seow, Chikako Kiyohara, Evgeny Imyanitov, Dongxin Lin, Michele Cote, Ping Yang, and R. Sobti.

Author contributions. ZY, HS, and JD designed the study. ZY, HS, JPTH, PP, and JD analyzed the data. ZY conducted statistical analyses. ZY and JD drafted the manuscript. ZY, HS, JPTH, PP, and JD edited the manuscript.

Abbreviations

CI

confidence interval

GST

glutathione S-transferase

Footnotes

Citation: Ye Z, Song H, Higgins JPT, Pharoah P, Danesh J (2006) Five glutathione S-transferase gene variants in 23,452 cases of lung cancer and 30,397 controls: Meta-analysis of 130 studies. PLoS Med 3(4): e91.

Funding: JD has been supported by the Raymond and Beverly Sackler Award in the Medical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  1. Ketterer B. Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis. Mutat Res. 1988;202:343–361. doi: 10.1016/0027-5107(88)90197-2. [DOI] [PubMed] [Google Scholar]
  2. Ketterer B, Harris JM, Talaska G, Meyer DJ, Pemble SE, et al. The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer. Environ Health Perspect. 1992;98:87–94. doi: 10.1289/ehp.929887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Hirvonen A. Polymorphisms of xenobiotic-metabolizing enzymes and susceptibility to cancer. Environ Health Perspect. 1999;107(Suppl 1):37–47. doi: 10.1289/ehp.99107s137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Kato S, Browman ED, Harrigan AM, Blomke B, Shields PG. Human lung carcinogen-DNA adduct levels mediated by genetic polymorphism in vivo. J Natl Cancer Inst. 1995;87:902–907. doi: 10.1093/jnci/87.12.902. [DOI] [PubMed] [Google Scholar]
  5. Rebbeck TR. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility . Cancer Epidemiol Biomarkers Prev. 1997;6:733–743. [PubMed] [Google Scholar]
  6. Alexandrie AK, Sundberg MI, Seidegard J, Tornling G, Rannug A. Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1 A study on host factors in relation to age at onset, gender, and histological cancer types . Carcinogenesis. 1994;15:1785–1790. doi: 10.1093/carcin/15.9.1785. [DOI] [PubMed] [Google Scholar]
  7. Alexandrie AK, Nyberg F, Warholm M, Rannug A. Influence of CYP1A1, GSTM1, GSTT1 and NQO1 genotypes and cumulative smoking dose on lung cancer risk in a Swedish population . Cancer Epidemiol Biomarkers Prev. 2004;13:908–914. [PubMed] [Google Scholar]
  8. Barnholtz-Sloan JS, Chakraborty R, Sellers TA, Schwartz AG. Examining population stratification via individual ancestry estimates versus self-reported race. Cancer Epidemiol Biomarkers Prev. 2005;14:1545–1551. doi: 10.1158/1055-9965.EPI-04-0832. [DOI] [PubMed] [Google Scholar]
  9. Belogubova EV, Togo AV, Kondratieva TV, Lemehov VG, Hanson KP, et al. GSTM1 genotypes in elderly tumor-free smokers and non-smokers . Lung Cancer. 2000;29:189–195. doi: 10.1016/s0169-5002(00)00120-3. [DOI] [PubMed] [Google Scholar]
  10. Belogubova EV, Togo AV, Karpova MB, Kuligina ES, Buslova KG, et al. A novel approach for assessment of cancer predisposing roles of GSTM1 and GSTT1 genes: Use of putatively cancer resistant elderly tumor-free smokers as the referents . Lung Cancer. 2004;43:259–266. doi: 10.1016/j.lungcan.2003.08.019. [DOI] [PubMed] [Google Scholar]
  11. Brockmoller J, Kerb R, Drakoulis N, Nitz M, Roots I. Genotype and phenotype of glutathione S-transferase class mu isoenzymes mu and psi in lung cancer patients and controls. Cancer Res. 1993;53:1004–1011. [PubMed] [Google Scholar]
  12. Butkiewicz D, Cole KJ, Phillips DH, Harris CC, Chorazy M. GSTM1, GSTP1, CYP1A1 and CYP2D6 polymorphisms in lung cancer patients from an environmentally polluted region of Poland: Correlation with lung DNA adduct levels . Eur J Cancer Prev. 1999;8:315–323. doi: 10.1097/00008469-199908000-00008. [DOI] [PubMed] [Google Scholar]
  13. Cajas-Salazar N, Sierra-Torres CH, Salama SA, Zwischenberger JB, Au WW. Combined effect of MPO, GSTM1 and GSTT1 polymorphisms on chromosome aberrations and lung cancer risk . Int J Hyg Environ Health. 2003;206:473–483. doi: 10.1078/1438-4639-00251. [DOI] [PubMed] [Google Scholar]
  14. Chan-Yeung M, Tan-Un KC, Ip MS, Tsang KW, Ho SP, et al. Lung cancer susceptibility and polymorphisms of glutathione-S-transferase genes in Hong Kong. Lung Cancer. 2004;45:155–160. doi: 10.1016/j.lungcan.2004.01.016. [DOI] [PubMed] [Google Scholar]
  15. Chen S, Xue K, Xu L, Ma G, Wu J. Polymorphisms of the CYP1A1 and GSTM1 genes in relation to individual susceptibility to lung carcinoma in Chinese population . Mutat Res. 2001;458:41–47. doi: 10.1016/s1383-5726(01)00011-5. [DOI] [PubMed] [Google Scholar]
  16. Cheng TJ, Christiani DC, Wiencke JK, Wain JC, Xu X, et al. Comparison of sister chromatid exchange frequency in peripheral lymphocytes in lung cancer cases and controls. Mutat Res. 1995;348:75–82. doi: 10.1016/0165-7992(95)00049-6. [DOI] [PubMed] [Google Scholar]
  17. Cote ML, Kardia SL, Wenzlaff AS, Land SJ, Schwartz AG. Combinations of glutathione S-transferase genotypes and risk of early-onset lung cancer in Caucasians and African Americans: A population-based study. Carcinogenesis. 2005;26:811–819. doi: 10.1093/carcin/bgi023. [DOI] [PubMed] [Google Scholar]
  18. Deakin M, Elder J, Hendrickse C, Peckham D, Baldwin D, et al. Glutathione S-transferase GSTT1 genotypes and susceptibility to cancer: Studies of interactions with GSTM1 in lung, oral, gastric, and colorectal cancers . Carcinogenesis. 1996;17:881–884. doi: 10.1093/carcin/17.4.881. [DOI] [PubMed] [Google Scholar]
  19. Dialyna IA, Miyakis S, Georgatou N, Spandidos DA. Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk . Oncol Rep. 2003;10:1829–1835. [PubMed] [Google Scholar]
  20. Dresler CM, Fratelli C, Babb J, Everley L, Evans AA, et al. Gender differences in genetic susceptibility for lung cancer. Lung Cancer. 2000;30:153–160. doi: 10.1016/s0169-5002(00)00163-x. [DOI] [PubMed] [Google Scholar]
  21. el Zein R, Zwischenberger JB, Wood TG, Abdel-Rahman SZ, Brekelbaum C, et al. Combined genetic polymorphism and risk for development of lung cancer. Mutat Res. 1997;381:189–200. doi: 10.1016/s0027-5107(97)00166-8. [DOI] [PubMed] [Google Scholar]
  22. Ford JG, Li Y, O'Sullivan MM, Demopoulos R, Garte S, et al. Glutathione S-transferase M1 polymorphism and lung cancer risk in African-Americans. Carcinogenesis. 2000;21:1971–1975. doi: 10.1093/carcin/21.11.1971. [DOI] [PubMed] [Google Scholar]
  23. Gallegos-Arreola MP, Gomez-Meda BC, Morgan-Villela G, Arechavaleta-Granell MR, Arnaud-Lopez L, et al. GSTT1 gene deletion is associated with lung cancer in Mexican patients . Dis Markers. 2003;19:259–261. doi: 10.1155/2004/826408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gao J, Ren C, Zhang Q. CYP2D6 and GSTM1 genetic polymorphism and lung cancer susceptibility . Zhonghua Zhong Liu Za Zhi. 1998;20:185–186. [PubMed] [Google Scholar]
  25. Gao Y, Zhang Q. Polymorphisms of the GSTM1 and CYP2D6 genes associated with susceptibility to lung cancer in Chinese . Mutat Res. 1999;444:441–449. doi: 10.1016/s1383-5718(99)00092-3. [DOI] [PubMed] [Google Scholar]
  26. Garcia-Closas M, Kelsey KT, Wiencke JK, Xu X, Wain JC, et al. A case-control study of cytochrome P450 1A1, glutathione S-transferase M1, cigarette smoking, and lung cancer susceptibility (Massachusetts, United States) Cancer Causes Control. 1997;8:544–553. doi: 10.1023/a:1018481910663. [DOI] [PubMed] [Google Scholar]
  27. Ge H, Lam WK, Lee J, Wong MP, Yew WW, et al. Analysis of L-myc and GSTM1 genotypes in Chinese non-small cell lung carcinoma patients . Lung Cancer. 1996;15:355–366. doi: 10.1016/0169-5002(95)00598-6. [DOI] [PubMed] [Google Scholar]
  28. Gsur A, Haidinger G, Hollaus P, Herbacek I, Madersbacher S, et al. Genetic polymorphisms of CYP1A1 and GSTM1 and lung cancer risk . Anticancer Res. 2001;21:2237–2242. [PubMed] [Google Scholar]
  29. Habalova V, Salagovic J, Kalina I, Stubna J. Combined analysis of polymorphisms in glutathione S-transferase M1 and microsomal epoxide hydrolase in lung cancer patients. Neoplasma. 2004;51:352–357. [PubMed] [Google Scholar]
  30. Harris MJ, Coggan M, Langton L, Wilson SR, Board PG. Polymorphism of the Pi class glutathione S-transferase in normal populations and cancer patients. Pharmacogenetics. 1998;8:27–31. doi: 10.1097/00008571-199802000-00004. [DOI] [PubMed] [Google Scholar]
  31. Harrison DJ, Cantlay AM, Rae F, Lamb D, Smith CA. Frequency of glutathione S-transferase M1 deletion in smokers with emphysema and lung cancer. Hum Exp Toxicol. 1997;16:356–360. doi: 10.1177/096032719701600703. [DOI] [PubMed] [Google Scholar]
  32. Hayashi S, Watanabe J, Kawajiri K. High susceptibility to lung cancer analyzed in terms of combined genotypes of P450IA1 and Mu-class glutathione S-transferase genes . Jpn J Cancer Res. 1992;83:866–870. doi: 10.1111/j.1349-7006.1992.tb01992.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Heckbert SR, Weiss NS, Hornung SK, Eaton DL, Motulsky AG. Glutathione S-transferase and epoxide hydrolase activity in human leukocytes in relation to risk of lung cancer and other smoking-related cancers. J Natl Cancer Inst. 1992;84:414–422. doi: 10.1093/jnci/84.6.414. [DOI] [PubMed] [Google Scholar]
  34. Hirvonen A, Husgafvel-Pursiainen K, Anttila S, Vainio H. The GSTM1 null genotype as a potential risk modifier for squamous cell carcinoma of the lung . Carcinogenesis. 1993;14:1479–1481. doi: 10.1093/carcin/14.7.1479. [DOI] [PubMed] [Google Scholar]
  35. Hong YS, Chang JH, Kwon OJ, Ham YA, Choi JH. Polymorphism of the CYP1A1 and glutathione-S-transferase gene in Korean lung cancer patients . Exp Mol Med. 1998;30:192–198. doi: 10.1038/emm.1998.28. [DOI] [PubMed] [Google Scholar]
  36. Hou SM, Ryberg D, Falt S, Deverill A, Tefre T, et al. GSTM1 and NAT2 polymorphisms in operable and non-operable lung cancer patients . Carcinogenesis. 2000;21:49–54. doi: 10.1093/carcin/21.1.49. [DOI] [PubMed] [Google Scholar]
  37. Jourenkova-Mironova N, Wikman H, Bouchardy C, Voho A, Dayer P, et al. Role of glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes in modulating susceptibility to smoking-related lung cancer . Pharmacogenetics. 1998;8:495–502. doi: 10.1097/00008571-199812000-00006. [DOI] [PubMed] [Google Scholar]
  38. Jourenkova N, Reinikanen M, Bouchardy C, Husgafvel-Pursiainen K, Dayer P, et al. Effects of glutathione S-transferases GSTM1 and GSTT1 genotypes on lung cancer risk in smokers . Pharmacogenetics. 1997;7:515–518. doi: 10.1097/00008571-199712000-00010. [DOI] [PubMed] [Google Scholar]
  39. Katoh T. The frequency of glutathione-S-transferase M1 (GSTM1) gene deletion in patients with lung and oral cancer . Sangyo Igaku. 1994;36:435–439. doi: 10.1539/joh1959.36.6_435. [DOI] [PubMed] [Google Scholar]
  40. Kawajiri K, Watanabe J, Eguchi H, Hayashi S. Genetic polymorphisms of drug-metabolizing enzymes and lung cancer susceptibility. Pharmacogenetics. 1995;5 Spec No:S70–S73. doi: 10.1097/00008571-199512001-00004. [DOI] [PubMed] [Google Scholar]
  41. Kelsey KT, Spitz MR, Zuo ZF, Wiencke JK. Polymorphisms in the glutathione S-transferase class mu and theta genes interact and increase susceptibility to lung cancer in minority populations (Texas, United States) Cancer Causes Control. 1997;8:554–559. doi: 10.1023/a:1018434027502. [DOI] [PubMed] [Google Scholar]
  42. Kihara M, Kihara M, Noda K. Risk of smoking for squamous and small cell carcinomas of the lung modulated by combinations of CYP1A1 and GSTM1 gene polymorphisms in a Japanese population . Carcinogenesis. 1995;16:2331–2336. doi: 10.1093/carcin/16.10.2331. [DOI] [PubMed] [Google Scholar]
  43. Kihara M, Noda K, Kihara M. Distribution of GSTM1 null genotype in relation to gender, age, and smoking status in Japanese lung cancer patients . Pharmacogenetics. 1995;5 Spec No:S74–S79. doi: 10.1097/00008571-199512001-00005. [DOI] [PubMed] [Google Scholar]
  44. Kihara M, Kihara M, Noda K. Lung cancer risk of the GSTM1 null genotype is enhanced in the presence of the GSTP1 mutated genotype in male Japanese smokers . Cancer Lett. 1999;137:53–60. doi: 10.1016/s0304-3835(98)00337-1. [DOI] [PubMed] [Google Scholar]
  45. Kiyohara C, Yamamura KI, Nakanishi Y, Takayama K, Hara N. Polymorphism in GSTM1, GSTT1 and GSTP1 and susceptibility to lung cancer in a Japanese population . Asian Pac J Cancer Prev. 2000;1:293–298. [PubMed] [Google Scholar]
  46. Kiyohara C, Wakai K, Mikami H, Sido K, Ando M, et al. Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of environmental tobacco smoke and lung cancer: A case-control study in Japanese nonsmoking women . Int J Cancer. 2003;107:139–144. doi: 10.1002/ijc.11355. [DOI] [PubMed] [Google Scholar]
  47. Lan Q, He X, Costa DJ, Tian L, Rothman N, et al. Indoor coal combustion emissions, GSTM1 and GSTT1 genotypes, and lung cancer risk: A case-control study in Xuan Wei, China . Cancer Epidemiol Biomarkers Prev. 2000;9:605–608. [PubMed] [Google Scholar]
  48. Luo C, Chen Q, Cao W, Cheng X. Combined analysis of polymorphisms of GSTM1 and mutations of p53 gene in the patients with lung cancer . J Clin Oncol. 2004;31:1218–1224. [Google Scholar]
  49. Le Marchand L, Sivaraman L, Pierce L, Seifried A, Lum A, et al. Associations of CYP1A1, GSTM1 and CYP2E1 polymorphisms with lung cancer suggest cell type specificities to tobacco carcinogens . Cancer Res. 1998;58:4858–4863. [PubMed] [Google Scholar]
  50. Lewis S, Brennan P, Nyberg F, Ahrens W, Constantinescu V, et al. Cruciferous vegetable intake, GSTM1 genotype, and lung cancer risk in a non-smoking population . IARC Sci Publ. 2002;156:507–508. [PubMed] [Google Scholar]
  51. Lewis SJ, Cherry NM, Niven RM, Barber PV, Povey AC. GSTM1, GSTT1 and GSTP1 polymorphisms and lung cancer risk . Cancer Lett. 2002;180:165–171. doi: 10.1016/s0304-3835(02)00028-9. [DOI] [PubMed] [Google Scholar]
  52. Li WY, Lai BT, Zhan XP. The relationship between genetic polymorphism of metabolizing enzymes and the genetic susceptibility to lung cancer. Zhonghua Liu Xing Bing Xue Za Zhi. 2004;25:1042–1045. [PubMed] [Google Scholar]
  53. Liang GY, Pu YP, Yin LH. Studies of the genes related to lung cancer susceptibility in Nanjing Han population, China. Yi Chuan. 2004;26:584–588. [PubMed] [Google Scholar]
  54. Liu G, Miller DP, Zhou W, Thurston SW, Fan R, et al. Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma . Cancer Res. 2001;61:8718–8722. [PubMed] [Google Scholar]
  55. London SJ, Daly AK, Cooper J, Navidi WC, Carpenter CL, et al. Polymorphism of glutathione S-transferase M1 and lung cancer risk among African-Americans and Caucasians in Los Angeles County, California. J Natl Cancer Inst. 1995;87:1246–1253. doi: 10.1093/jnci/87.16.1246. [DOI] [PubMed] [Google Scholar]
  56. London SJ, Yuan JM, Chung FL, Gao YT, Coetzee GA, et al. Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: A prospective study of men in Shanghai, China. Lancet. 2000;356:724–729. doi: 10.1016/S0140-6736(00)02631-3. [DOI] [PubMed] [Google Scholar]
  57. Lu W, Xing D, Qi J, Tan W, Miao X, et al. Genetic polymorphism in myeloperoxidase but not GSTM1 is associated with risk of lung squamous cell carcinoma in a Chinese population . Int J Cancer. 2002;102:275–279. doi: 10.1002/ijc.10712. [DOI] [PubMed] [Google Scholar]
  58. Malats N, Camus-Radon AM, Nyberg F, Ahrens W, Constantinescu V, et al. Lung cancer risk in nonsmokers and GSTM1 and GSTT1 genetic polymorphism . Cancer Epidemiol Biomarkers Prev. 2000;9:827–833. [PubMed] [Google Scholar]
  59. Miller DP, Liu G, de Lynch VI TJ, Wain JC, et al. Combinations of the variant genotypes of GSTP1, GSTM1 and p53 are associated with an increased lung cancer risk . Cancer Res. 2002;62:2819–2823. [PubMed] [Google Scholar]
  60. Moreira A, Martins G, Monteiro MJ, Alves M, Dias J, et al. Glutathione S-transferase mu polymorphism and susceptibility to lung cancer in the Portuguese population. Teratog Carcinog Mutagen. 1996;16:269–74. doi: 10.1002/(SICI)1520-6866(1996)16:5<269::AID-TCM3>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  61. Nakachi K, Imai K, Hayashi S, Kawajiri K. Polymorphisms of the CYP1A1 and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population . Cancer Res. 1993;53:2994–2999. [PubMed] [Google Scholar]
  62. Nazar-Stewart V, Vaughan TL, Stapleton P, Van Loo J, Nicol-Blades B, et al. A population-based study of glutathione S-transferase M1, T1, and P1 genotypes and risk for lung cancer. Lung Cancer. 2003;40:247–258. doi: 10.1016/s0169-5002(03)00076-x. [DOI] [PubMed] [Google Scholar]
  63. Nyberg F, Hou SM, Hemminki K, Lambert B, Pershagen G. Glutathione S-transferase mu1 and N-acetyltransferase 2 genetic polymorphisms and exposure to tobacco smoke in nonsmoking and smoking lung cancer patients and population controls. Cancer Epidemiol Biomarkers Prev. 1998;7:875–883. [PubMed] [Google Scholar]
  64. Ozturk O, Isbir T, Yaylim I, Kocaturk CI, Gurses A. GST M1 and CYP1A1 gene polymorphism and daily fruit consumption in Turkish patients with non-small cell lung carcinomas . In Vivo. 2003;17:625–632. [PubMed] [Google Scholar]
  65. Perera FP, Mooney LA, Stampfer M, Phillips DH, Bell DA, et al. Associations between carcinogen-DNA damage, glutathione S-transferase genotypes, and risk of lung cancer in the prospective Physicians' Health Cohort Study. Carcinogenesis. 2002;23:1641–1646. doi: 10.1093/carcin/23.10.1641. [DOI] [PubMed] [Google Scholar]
  66. Persson I, Johansson I, Lou YC, Yue QY, Duan LS, et al. Genetic polymorphism of xenobiotic metabolizing enzymes among Chinese lung cancer patients. Int J Cancer. 1999;81:325–329. doi: 10.1002/(sici)1097-0215(19990505)81:3<325::aid-ijc2>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  67. Pinarbasi H, Silig Y, Cetinkaya O, Seyfikli Z, Pinarbasi E. Strong association between the GSTM1-null genotype and lung cancer in a Turkish population. Cancer Genet Cytogenet. 2003;146:125–129. doi: 10.1016/s0165-4608(03)00059-1. [DOI] [PubMed] [Google Scholar]
  68. Quinones L, Lucas D, Godoy J, Caceres D, Berthou F, et al. CYP1A1, CYP2E1 and GSTM1 genetic polymorphisms. The effect of single and combined genotypes on lung cancer susceptibility in Chilean people . Cancer Lett. 2001;174:35–44. doi: 10.1016/s0304-3835(01)00686-3. [DOI] [PubMed] [Google Scholar]
  69. Reszka E, Wasowicz W, Rydzynski K, Szeszenia-Dabrowska N, Szymczak W. Glutathione S-transferase M1 and P1 metabolic polymorphism and lung cancer predisposition. Neoplasma. 2003;50:357–362. [PubMed] [Google Scholar]
  70. Risch A, Wikman H, Thiel S, Schmezer P, Edler L, et al. Glutathione-S-transferase M1, M3, T1, and P1 polymorphisms and susceptibility to non-small-cell lung cancer subtypes and hamartomas. Pharmacogenetics. 2001;11:757–764. doi: 10.1097/00008571-200112000-00003. [DOI] [PubMed] [Google Scholar]
  71. Ruano-Ravina A, Figueiras A, Loidi L, Barros-Dios JM. GSTM1 and GSTT1 polymorphisms, tobacco, and risk of lung cancer: A case-control study from Galicia, Spain . Anticancer Res. 2003;23:4333–4337. [PubMed] [Google Scholar]
  72. Ryberg D, Skaug V, Hewer A, Phillips DH, Harries LW, et al. Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk. Carcinogenesis. 1997;18:1285–1289. doi: 10.1093/carcin/18.7.1285. [DOI] [PubMed] [Google Scholar]
  73. Saarikoski ST, Voho A, Reinikainen M, Anttila S, Karjalainen A, et al. Combined effect of polymorphic GST genes on individual susceptibility to lung cancer . Int J Cancer. 1998;77:516–521. doi: 10.1002/(sici)1097-0215(19980812)77:4<516::aid-ijc7>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  74. Salagovic J, Kalina I, Stubna J, Habalova V, Hrivnak M, et al. Genetic polymorphism of glutathione S-transferases M1 and T1 as a risk factor in lung and bladder cancers. Neoplasma. 1998;45:312–317. [PubMed] [Google Scholar]
  75. Schneider J, Bernges U, Philipp M, Woitowitz HJ. GSTM1, GSTT1 and GSTP1 polymorphism and lung cancer risk in relation to tobacco smoking . Cancer Lett. 2004;208:65–74. doi: 10.1016/j.canlet.2004.01.002. [DOI] [PubMed] [Google Scholar]
  76. Sgambato A, Campisi B, Zupa A, Bochicchio A, Romano G, et al. Glutathione S-transferase (GST) polymorphisms as risk factors for cancer in a highly homogeneous population from southern Italy . Anticancer Res. 2002;22:3647–3652. [PubMed] [Google Scholar]
  77. Sobti RC, Sharma S, Joshi A, Jindal SK, Janmeja A. Genetic polymorphism of the CYP1A1, CYP2E1, GSTM1 and GSTT1 genes and lung cancer susceptibility in a north Indian population . Mol Cell Biochem. 2004;266:1–9. doi: 10.1023/b:mcbi.0000049127.33458.87. [DOI] [PubMed] [Google Scholar]
  78. Sorensen M, Autrup H, Tjonneland A, Overvad K, Raaschou-Nielsen O. Glutathione S-transferase T1 null-genotype is associated with an increased risk of lung cancer. Int J Cancer. 2004;110:219–224. doi: 10.1002/ijc.20075. [DOI] [PubMed] [Google Scholar]
  79. Spitz MR, Duphorne CM, Detry MA, Pillow PC, Amos CI, et al. Dietary intake of isothiocyanates: Evidence of a joint effect with glutathione S-transferase polymorphisms in lung cancer risk. Cancer Epidemiol Biomarkers Prev. 2000;9:1017–1020. [PubMed] [Google Scholar]
  80. Stucker I, Hirvonen A, de Cabelguenne WI, Mitrunen K, et al. Genetic polymorphisms of glutathione S-transferases as modulators of lung cancer susceptibility. Carcinogenesis. 2002;23:1475–1481. doi: 10.1093/carcin/23.9.1475. [DOI] [PubMed] [Google Scholar]
  81. Sun GF, Shimojo N, Pi JB, Lee S, Kumagai Y. Gene deficiency of glutathione S-transferase mu isoform associated with susceptibility to lung cancer in a Chinese population. Cancer Lett. 1997;113:1669–1672. doi: 10.1016/s0304-3835(97)04612-0. [DOI] [PubMed] [Google Scholar]
  82. Sunaga N, Kohno T, Yanagitani N, Sugimura H, Kunitoh H, et al. Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility . Cancer Epidemiol Biomarkers Prev. 2002;11:730–738. [PubMed] [Google Scholar]
  83. Sweeney C, Nazar-Stewart V, Stapleton PL, Eaton DL, Vaughan TL. Glutathione S-transferase M1, T1, and P1 polymorphisms and survival among lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2003;12:527–533. [PubMed] [Google Scholar]
  84. Tang DL, Rundle A, Warburton D, Santella RM, Tsai WY, et al. Associations between both genetic and environmental biomarkers and lung cancer: Evidence of a greater risk of lung cancer in women smokers. Carcinogenesis. 1998;19:1949–1953. doi: 10.1093/carcin/19.11.1949. [DOI] [PubMed] [Google Scholar]
  85. To-Figueras J, Gene M, Gomez-Catalan J, Galan MC, Fuentes M, et al. Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms and lung cancer risk among Northwestern Mediterraneans . Carcinogenesis. 1997;18:1529–1533. doi: 10.1093/carcin/18.8.1529. [DOI] [PubMed] [Google Scholar]
  86. To-Figueras J, Gene M, Gomez-Catalan J, Pique E, Borrego N, et al. Genetic polymorphism of glutathione S-transferase P1 gene and lung cancer risk. Cancer Causes Control. 1999;10:65–70. doi: 10.1023/a:1008811824890. [DOI] [PubMed] [Google Scholar]
  87. To-Figueras J, Gene M, Gomez-Catalan J, Pique E, Borrego N, et al. Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1. Cancer Lett. 2001;173:155–162. doi: 10.1016/s0304-3835(01)00626-7. [DOI] [PubMed] [Google Scholar]
  88. Tsai YY, McGlynn KA, Hu Y, Cassidy AB, Arnold J, et al. Genetic susceptibility and dietary patterns in lung cancer. Lung Cancer. 2003;41:269–281. doi: 10.1016/s0169-5002(03)00238-1. [DOI] [PubMed] [Google Scholar]
  89. Wang BG, Chen SD, Zhou WP, Zeng M, Li ZB, et al. A case control study on the impact of CYP450 MSPI and GST-M1 polymorphisms on the risk of lung cancer . Zhonghua Zhong Liu Za Zhi. 2004;26:93–97. [PubMed] [Google Scholar]
  90. Wang J, Deng Y, Cheng J, Ding J, Tokudome S. GST genetic polymorphisms and lung adenocarcinoma susceptibility in a Chinese population . Cancer Lett. 2003;201:185–193. doi: 10.1016/s0304-3835(03)00480-4. [DOI] [PubMed] [Google Scholar]
  91. Wang J, Deng Y, Li L, Kuriki K, Ding J, et al. Association of GSTM1, CYP1A1 and CYP2E1 genetic polymorphisms with susceptibility to lung adenocarcinoma: A case-control study in Chinese population . Cancer Sci. 2003;94:448–452. doi: 10.1111/j.1349-7006.2003.tb01463.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Wang LI, Giovannucci EL, Hunter D, Neuberg D, Su L, et al. Dietary intake of cruciferous vegetables, Glutathione S-transferase (GST) polymorphisms, and lung cancer risk in a Caucasian population . Cancer Causes Control. 2004;15:977–985. doi: 10.1007/s10552-004-1093-1. [DOI] [PubMed] [Google Scholar]
  93. Wang Y, Spitz MR, Schabath MB, Ali-Osman F, Mata H, et al. Association between glutathione S-transferase p1 polymorphisms and lung cancer risk in Caucasians: A case-control study. Lung Cancer. 2003;40:25–32. doi: 10.1016/s0169-5002(02)00537-8. [DOI] [PubMed] [Google Scholar]
  94. Wang YC, Chen CY, Wang HJ, Chen SK, Chang YY, et al. Influence of polymorphism at p53, CYP1A1 and GSTM1 loci on p53 mutation and association of p53 mutation with prognosis in lung cancer . Zhonghua Yi Xue Za Zhi (Taipei) 1999;62:402–410. [PubMed] [Google Scholar]
  95. Woodson K, Stewart C, Barrett M, Bhat NK, Virtamo J, et al. Effect of vitamin intervention on the relationship between GSTM1 smoking, and lung cancer risk among male smokers . Cancer Epidemiol Biomarkers Prev. 1999;8:965–970. [PubMed] [Google Scholar]
  96. Yang P, Bamlet WR, Ebbert JO, Taylor WR, de Andrade M. Glutathione pathway genes and lung cancer risk in young and old populations. Carcinogenesis. 2004;25:1935–1944. doi: 10.1093/carcin/bgh203. [DOI] [PubMed] [Google Scholar]
  97. Yang XR, Wacholder S, Xu Z, Dean M, Clark V, et al. CYP1A1 and GSTM1 polymorphisms in relation to lung cancer risk in Chinese women . Cancer Lett. 2004;214:197–204. doi: 10.1016/j.canlet.2004.06.040. [DOI] [PubMed] [Google Scholar]
  98. Zhao B, Seow A, Lee EJ, Poh WT, Teh M, et al. Dietary isothiocyanates, glutathione S-transferase -M1, -T1 polymorphisms and lung cancer risk among Chinese women in Singapore. Cancer Epidemiol Biomarkers Prev. 2001;10:1063–1067. [PubMed] [Google Scholar]
  99. Zhong S, Howie AF, Ketterer B, Taylor J, Hayes JD, et al. Glutathione S-transferase mu locus: Use of genotyping and phenotyping assays to assess association with lung cancer susceptibility. Carcinogenesis. 1991;12:1533–1537. doi: 10.1093/carcin/12.9.1533. [DOI] [PubMed] [Google Scholar]
  100. Gao J, Ren C, Zhang Q. CYP2D6 and GSTM1 genetic polymorphism and lung cancer susceptibility . Zhonghua Zhong Lu Zha Zhi. 1998;5:185–186. [PubMed] [Google Scholar]
  101. Hu Y, Gao Y, Zhang Q. Genetic polymorphisms of CYP1A1, 2D6 and GSTM1 related with susceptibility to lung cancer . Tumor (Shanghai) 1998;18:269–271. [Google Scholar]
  102. Qu T, Shi Y, Peter S. The genotypes of cytochrome P450 1A1 and GSTM1 in non-smoking female lung cancer . Tumor (Shanghai) 1998;18:80–82. [Google Scholar]
  103. Xue K, Xu L, Cheng S, Ma G, Wu Z. Polymorphism of CYP1A1, GSTM1 and lung cancer susceptibility in the Chinese population . Teratog Carcinogen Mutagen. 1999;11:326. [Google Scholar]
  104. Xue K, Xu L, Chen S, Ma G, Wu J. Polymorphisms of the CYP1A1 and GSTM1 genes and their combined effects on individual susceptibility to lung cancer in a Chinese population . Chin J Med Genet. 2001;18:125–127. [PubMed] [Google Scholar]
  105. Zhang L, Wang X, Hao X, Liu Z. Relationship between susceptibility to lung cancer and genetic polymorphism in P4501A1, GSTM1 . J Clin Oncol. 2002;29:536–540. [Google Scholar]
  106. Shi Y, Zhou X, Zhou Y. Analysis of CYP2E1, GSTM1 genetic polymorphisms in relation to human lung cancer and esophageal carcinoma . J Huazhong Uni Sci Tech. 2002;31:14–17. [Google Scholar]
  107. Qiao G, Wu Y, Zhen W, Giang R, Wang S, et al. A case-control study of GSTM1 deficiency and non-small-cell lung cancer . Acad J SUMS. 2002;23:25–27. [Google Scholar]
  108. Zhang J, Hu Y, Yu C, Wang S. Polymorphism of GSTM1 and T1 and lung cancer susceptibility . Chin J Pathophysiology. 2002;18:352–355. [Google Scholar]
  109. Zhang J, Hu Y, H C, Wang S. Study on genetic polymorphisms of GSTM1 and GSTT1 related with inherent susceptibility to lung cancer in women . Chin J Public Health. 2002;18:273–275. [Google Scholar]
  110. Chan Y, Wang X, Wang X, Liang Z. A study of genetic polymorphism of GSTM1 gene in normal population and lung cancer population in Yunnan . J Yunnan Normal University. 2002;22:52–54. [Google Scholar]
  111. Chen L, Sun H, Xu Y. Study on the allele frequency of GSTM1 gene in normal Han population in Wannan area and the relationship between GSTM1 genotype and the risk of lung cancer . J Wannan Medical College. 2003;22:13–16. [Google Scholar]
  112. Xian X, Chen S, Wang B. The relationship between polymorphism of GSTM1 and susceptibility to lung cancer . Practical Preventive Medicine. 2003;10:635–637. [Google Scholar]
  113. Ye W, Chen Q, Chen S. Study on relationship between GSTM1 polymorphism, diet factors, and lung cancer . Chin J Public Health. 2004;20:1120–1121. [Google Scholar]
  114. Chen M, Chen S, Wang B. A case-control study of the impact of glutathione S-transferase M1 on the risk of lung cancer. Chin Tumor. 2004;13:686–688. [Google Scholar]
  115. Cao Y, Chen H, Liu X. Study on the relationship between the genetic polymorphisms of GSTM1 and GSTT1 genes and lung cancer susceptibility in the population of Hunan province of China . Life Science Res. 2004;8:126–132. [Google Scholar]
  116. Wang N, Wu Y, Wu Y, Zhuang D. Study on relationship between GSTM1, GSTT1 gene deficiency, and lung cancer susceptibility . Health Serv Res. 2004;33:586–588. [Google Scholar]
  117. Dong C, Yang Q, Wang M, Dong Q. A study on the relationship between polymorphism of CYP1A1 lack of GSTM1 and susceptibility to lung cancer . J Occup Environ Med. 2004;21:440–442. [Google Scholar]
  118. Li D, Zhou Q, Yuan T. Study on the association between genetic polymorphism of CYP2E1, GSTM1 and susceptibility of lung cancer . Chin J Cancer Res. 2005;8:14–19. doi: 10.3779/j.issn.1009-3419.2005.01.03. [DOI] [PubMed] [Google Scholar]
  119. Yuan T, Zhou Q, Zhu W. Relationship between genetic polymorphism of GSTT1 gene and inherent susceptibility to lung cancer in Han population in Sichuan, China . Chin J Cancer Res. 2005;8:107–111. doi: 10.3779/j.issn.1009-3419.2005.02.07. [DOI] [PubMed] [Google Scholar]
  120. Lin P, Hsueh YM, Ko JL, Liang YF, Tsai KJ, et al. Analysis of NQO1, GSTP1 and MnSOD genetic polymorphisms on lung cancer risk in Taiwan . Lung Cancer. 2003;40:123–129. doi: 10.1016/s0169-5002(03)00027-8. [DOI] [PubMed] [Google Scholar]
  121. Bonner MR, Rothman N, Mumford JL, He X, Shen M, et al. Green tea consumption, genetic susceptibility, PAH-rich smoky coal, and the risk of lung cancer. Mutat Res. 2005;582:53–60. doi: 10.1016/j.mrgentox.2004.12.008. [DOI] [PubMed] [Google Scholar]
  122. el Zein R, Conforti-Froes N, Au WW. Interactions between genetic predisposition and environmental toxicants for development of lung cancer. Environ Mol Mutagen. 1997;30:196–204. doi: 10.1002/(sici)1098-2280(1997)30:2<196::aid-em12>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  123. Hou SM, Falt S, Yang K, Nyberg F, Pershagen G, et al. Differential interactions between GSTM1 and NAT2 genotypes on aromatic DNA adduct level and HPRT mutant frequency in lung cancer patients and population controls . Cancer Epidemiol Biomarkers Prev. 2001;10:133–140. [PubMed] [Google Scholar]
  124. Hou SM, Falt S, Nyberg F. Glutathione S-transferase T1-null genotype interacts synergistically with heavy smoking on lung cancer risk. Environ Mol Mutagen. 2001;38:83–86. doi: 10.1002/em.1054. [DOI] [PubMed] [Google Scholar]
  125. Kihara M, Kihara M, Noda K. Lung cancer risk of GSTM1 null genotype is dependent on the extent of tobacco smoke exposure . Carcinogenesis. 1994;15:415–418. doi: 10.1093/carcin/15.2.415. [DOI] [PubMed] [Google Scholar]
  126. Lan Q, He X, Costa D, Tian W. Glutathione S-transferase GSTM1 and GSTT1 genotypes and susceptibility to lung cancer . Wei Sheng Yan Jiu. 1999;28:9–11. [PubMed] [Google Scholar]
  127. London SJ, Yuan JM, Coetzee GA, Gao YT, Ross RK, et al. CYP1A1 I462V genetic polymorphism and lung cancer risk in a cohort of men in Shanghai, China . Cancer Epidemiol Biomarkers Prev. 2000;9:987–991. [PubMed] [Google Scholar]
  128. Miller DP, Neuberg D, de Vivo I, Wain JC, Lynch TJ, et al. Smoking and the risk of lung cancer: Susceptibility with GSTP1 polymorphisms . Epidemiology. 2003;14:545–551. doi: 10.1097/01.ede.0000073120.46981.24. [DOI] [PubMed] [Google Scholar]
  129. Stucker I, de Waziers I, Cenee S, Bignon J, Depierre A, et al. GSTM1 smoking, and lung cancer: A case-control study . Int J Epidemiol. 1999;28:829–835. doi: 10.1093/ije/28.5.829. [DOI] [PubMed] [Google Scholar]
  130. Stucker I, Jacquet M, de Waziers I, Cenee S, Beaune P, et al. Relation between inducibility of CYP1A1, GSTM1 and lung cancer in a French population . Pharmacogenetics. 2000;10:617–627. doi: 10.1097/00008571-200010000-00005. [DOI] [PubMed] [Google Scholar]
  131. Sun G, Pi J, Zheng Q. The study of GST mu gene deletion as the hereditary marker for susceptibility to lung cancer . Zhonghua Jie He He Hu Xi Za Zhi. 1995;18:167–169. [PubMed] [Google Scholar]
  132. To-Figueras J, Gene M, Gomez-Catalan J, Pique E, Borrego N, et al. Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1. Cancer Lett. 2001;173:155–162. doi: 10.1016/s0304-3835(01)00626-7. [DOI] [PubMed] [Google Scholar]
  133. Wenzlaff AS, Cote ML, Bock CH, Land SJ, Schwartz AG. GSTM1, GSTT1 and GSTP1 polymorphisms, environmental tobacco smoke exposure and risk of lung cancer among never smokers: A population-based study . Carcinogenesis. 2005;26:395–401. doi: 10.1093/carcin/bgh326. [DOI] [PubMed] [Google Scholar]
  134. Xue K, Xu L, Chen S, Ma G, Wu J. Polymorphisms of the CYP1A1 and GSTM1 genes and their combined effects on individual susceptibility to lung cancer in a Chinese population . Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2001;18:125–127. [PubMed] [Google Scholar]
  135. Yamamura K, Kiyohara C, Nakanishi Y, Takayama K, Hara N. Lung cancer risk and genetic polymorphism at the glutathione S-transferase P1 locus in male Japanese. Fukuoka Igaku Zasshi. 2000;91:203–206. [PubMed] [Google Scholar]
  136. Lan Q, He X. Molecular epidemiological studies on the relationship between indoor coal burning and lung cancer in Xuan Wei, China. Toxicology. 2004;198:301–305. doi: 10.1016/j.tox.2004.02.006. [DOI] [PubMed] [Google Scholar]
  137. Gao J, Chen C, Zhang Q. Study on the relationship between GSTM1 genetic polymorphism and lung cancer, colon cancer susceptibility . J Zhejiang Medical College. 1998;8:446–447. [Google Scholar]
  138. Gao J, Zhang Q. Study on the relationship between GSTM1 polymorphism and lung cancer susceptibility . Teratog Carcinog and Mutagen. 1998;10:149–151. [Google Scholar]
  139. Gao J, Zhang Q. Study on the polymorphisms of GSTM1 and CYP2D6 genes associated with susceptibility to lung cancer in Chinese . Chin J Public Health. 1999;15:488–490. doi: 10.1016/s1383-5718(99)00092-3. [DOI] [PubMed] [Google Scholar]
  140. Chen S, Xu L, Ma G, Wu J, Xue K. Identication of genetic polymorphism of CYP1A1 and GSTM1 in lung cancer patients by using allele-specific PCR and multiplex differential PCR . Teratog Carcinog Mutagen. 1999;11:119–122. [Google Scholar]
  141. Wang N, Zhuang D, Wu Y. Research on relationship between GSTM1 gene deletion and lung cancer genetic susceptibility . J Henan Univ Sci Tech. 2005;23:7–8. [Google Scholar]
  142. Ye W, Chen S, Chen Q. Interaction between serum selenium level and polymorphism of GSTM1 in lung cancer . Acta Nutrimenta Sinica. 2005;27:17–19. [Google Scholar]
  143. Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J. Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins . J Biol Chem. 1997;272:10004–10012. doi: 10.1074/jbc.272.15.10004. [DOI] [PubMed] [Google Scholar]
  144. Becker KG, Jedlicka P, Templeton NS, Liotta L, Ozato K. Characterization of hUCRBP (YY1, NF-E1, delta): A transcription factor that binds the regulatory regions of many viral and cellular genes. Gene. 1994;150:259–266. doi: 10.1016/0378-1119(94)90435-9. [DOI] [PubMed] [Google Scholar]
  145. Inskip A, Elexperu-Camiruaga J, Buxton N, Dias PS, MacIntosh J, et al. Identification of polymorphism at the glutathione S-transferase, GSTM3 locus: Evidence for linkage with GSTM1*A . Biochem J. 1995;312(Pt 3):713–716. doi: 10.1042/bj3120713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  146. Yengi L, Inskip A, Gilford J, Alldersea J, Bailey L, et al. Polymorphism at the glutathione S-transferase locus GSTM3: Interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneouse basal cell carcinoma. Cancer Res. 1996;56:1974–1977. [PubMed] [Google Scholar]
  147. McWilliams JE, Sanderson BJ, Harris EL, Richert-Boe KE, Henner WD. Glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk . Cancer Epidemiol Biomarkers Prev. 1995;4:589–594. [PubMed] [Google Scholar]
  148. Houlston RS. Glutathione S-transferase M1 status and lung cancer risk: A meta-analysis. Cancer Epidemiol Biomarkers Prev. 1999;8:675–682. [PubMed] [Google Scholar]
  149. Benhamou S, Lee WJ, Alexandrie AK, Boffetta P, Bouchardy CD, et al. Meta- and pooled-analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk. Carcinogenesis. 2002;23:1343–1350. doi: 10.1093/carcin/23.8.1343. [DOI] [PubMed] [Google Scholar]
  150. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  151. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
  152. Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomized clinical trials. Stat Med. 1991;10:1665–1677. doi: 10.1002/sim.4780101105. [DOI] [PubMed] [Google Scholar]
  153. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–1101. [PubMed] [Google Scholar]
  154. Duval S, Tweedie R. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. JASA. 2000;95:89–98. doi: 10.1111/j.0006-341x.2000.00455.x. [DOI] [PubMed] [Google Scholar]
  155. Wu X, Zhao H, Suk R, Christiani DC. Genetic susceptibility to tobacco-related cancer. Oncogene. 2004;23:6500–6523. doi: 10.1038/sj.onc.1207811. [DOI] [PubMed] [Google Scholar]
  156. Wall JD, Pritchard JK. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet. 2003;4:587–597. doi: 10.1038/nrg1123. [DOI] [PubMed] [Google Scholar]
  157. Tsunoda T, Lathrop GM, Sekine A, Yamada R, Takahashi A, et al. Variation of gene-based SNPs and linkage disequilibrium patterns in the human genome. Hum Mol Genet. 2004;13:1623–1632. doi: 10.1093/hmg/ddh177. [DOI] [PubMed] [Google Scholar]
  158. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years' observations on male British doctors. BMJ. 2004;328:1519–1528. doi: 10.1136/bmj.38142.554479.AE. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1. Funnel Plot of Studies of GSTM1 Null Polymorphism and Lung Cancer Showing a Possible Excess of Smaller Studies with Strikingly Positive Findings beyond the 95% CI; Begg's Test, p < 0.0001 .

(52 KB PPT).

Click here for additional data file. (52.5KB, ppt)
Figure S2. Trimmed and Filled Funnel Plot of GSTM1 Null Polymorphism and Lung Cancer .

The hollow diamonds are the actual studies included in the meta-analysis, the squares are the Trimmed and Filled studies required to achieve symmetry.

(56 KB PPT).

Click here for additional data file. (56KB, ppt)
Table S1. Characteristics of Genetic Association Studies of Five GST Polymorphisms in the Present Meta-Analyses .

(670 KB DOC).

Click here for additional data file. (670KB, doc)

Articles from PLoS Medicine are provided here courtesy of PLOS

RESOURCES