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American Journal of Epidemiology Advance Access originally published online on February 12, 2008
American Journal of Epidemiology 2008 167(7):759-774; doi:10.1093/aje/kwm383
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Glutathione S-Transferase M1 (GSTM1) Polymorphisms and Lung Cancer: A Literature-based Systematic HuGE Review and Meta-Analysis

C. Carlsten1,2, G. S. Sagoo3,4, A. J. Frodsham3,4, W. Burke5,6 and J. P. T. Higgins3,4

1 Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
2 School of Environmental Health, University of British Columbia, Vancouver, British Columbia, Canada
3 United Kingdom HuGENet Coordinating Centre, Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom
4 MRC Biostatistics Unit, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
5 Department of Medicine, School of Medicine, University of Washington, Seattle, WA
6 Center for Ecogenetics and Environmental Health, University of Washington, Seattle, WA

Correspondence to Dr. Chris Carlsten, Vancouver General Hospital, 2775 Laurel Street, 7th Floor (The Lung Center), Vancouver, British Columbia V5Z 1M9, Canada (e-mail: chris.carlsten{at}vch.ca).

Received for publication July 5, 2007. Accepted for publication December 7, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
Multiple genes have been studied for potential associations with lung cancer. The gene most frequently associated with increased risk has been glutathione S-transferase M1 (GSTM1). The glutathione S-transferase enzyme family is known to catalyze detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. In this review, the authors summarize the available evidence associating lung cancer with the GSTM1 gene. They describe results from an updated meta-analysis of 98 published genetic association studies investigating the relation between the GSTM1 null variant and lung cancer risk including 19,638 lung cancer cases and 25,266 controls (counting cases and controls in each study only once). All studies considered, the GSTM1 null variant was associated with an increased risk of lung cancer (odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.14, 1.30), but no increase in risk was seen (OR = 1.01, 95% CI: 0.91, 1.12) when only the five largest studies (>500 cases each) were considered. Furthermore, while GSTM1 null status conferred a significantly increased risk of lung cancer to East Asians (OR = 1.38, 95% CI: 1.24, 1.55), such a genotype did not confer increased risk to Caucasians. More data regarding the predictive value of GSTM1 genetic testing are needed before population-based testing may be reasonably considered.

epidemiology; genetics; genome; human; glutathione S-transferase M1; glutathione transferase; GSTM1; lung neoplasms; meta-analysis

Abbreviations: CI, confidence interval; CYP, cytochrome P-450; CYP1A1, cytochrome P-450 1A1; GST, glutathione S-transferase; GSTM1, glutathione S-transferase M1; GSTT1, glutathione S-transferase T1; HuGE, Human Genome Epidemiology; HuGENet, Human Genome Epidemiology Network; OR, odds ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
The association between the glutathione S-transferase M1 (GSTM1) gene and lung cancer has been investigated in numerous epidemiologic studies since glutathione S-transferase (GST) was first suggested as a potential marker for susceptibility to lung cancer in 1986 (1). Here we evaluate the evidence for an association between the GSTM1 null polymorphism and lung cancer using methods developed by the Human Genome Epidemiology Network (HuGENet) and the Cochrane Collaboration (2), as listed in the HuGENet HuGE Review Handbook (3). We follow the full Human Genome Epidemiology (HuGE) review format (Appendix B in the HuGENet HuGE Review Handbook (3)).


   GENE VARIANTS
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
The GSTs [EC 2.5.1.18 [EC] (4)] are a family of cytosolic enzymes known to catalyze the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress, by conjugation with glutathione (5). This conjugation reaction also facilitates excretion and thus constitutes a detoxification step. In addition to this role in phase II detoxification, GSTs are able to modulate the induction of other enzymes and proteins important in cellular functions, such as DNA repair, and are therefore important in maintaining genomic integrity (5). The GST enzymes could potentially play an important role in susceptibility to cancer. Five distinct loci (alpha, mu (M), theta, pi, and gamma) are known to encode the GST enzymes. Here we consider the relation between the GSTM1 gene and lung cancer.

GSTM1 (OMIM number 138350 [OMIM] (6)) has been mapped to the GST mu gene cluster on chromosome 1p13.3. Two variants in GSTM1 have been identified: a deletion and a substitution. The alleles of the substitution variant differ by a C-to-G transition at base position 534, resulting in a lysine-to-asparagine substitution at amino acid 172 (7, 8). The deletion (GSTM1 null variant) has been examined extensively in epidemiologic studies. Persons with a homozygous deletion of the GSTM1 locus have no enzymatic functional activity. Phenotype assays have confirmed this lack of function by demonstrating a strong concordance (≥94 percent) between phenotype and genotype (9, 10). The GSTM1 gene and the null variant have been the focus of previous HuGE reviews of colorectal cancer (9) and squamous-cell carcinoma of the head and neck (11) and previous pooled and meta-analyses (table 1).


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  		TABLE 1. Characteristics and findings of previously conducted meta- and pooled analyses of glutathione S-transferase M1 (GSTM1) polymorphisms and lung cancer

 

   GENE VARIANT FREQUENCY
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
Several extensive reviews have summarized data on the frequency of the GSTM1 null genotype (8, 9, 11). The percentages of persons who were homozygous for the GSTM1 null genotype across control groups in all studies ranged from 18 to 66, with a median of 50 (see Web table 1, which is posted on the Journal's website (http://aje.oxfordjournals.org/)). In the studies reporting controls as ethnically Caucasian, the frequency of the GSTM1 null genotype ranged from 42 percent to 61 percent (median, 50 percent). In studies reporting controls as ethnically of East Asian descent (such as Chinese and Japanese), the frequency of the GSTM1 null genotype ranged from 36 percent to 66 percent (median, 51 percent). Studies conducted in Turkish populations showed both the lowest (18 percent) and highest (66 percent) reported frequencies of the GSTM1 null genotype. GSTM1 heterozygosity is very rarely reported because of the dominant effect of the null mutation in substantially reducing protein function.


   DISEASE
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
Lung cancer has been the most common cancer in the world since 1985 (12). In 2002, 1.35 million new cases of lung cancer were diagnosed, representing more than 12 percent of all new cancer cases. Lung cancer is also the most common cause of death from cancer, with 1.18 million deaths, accounting for 17.6 percent of the world total (12). Cancer rates have peaked among men in many parts of the world, but rates are continuing to rise among women, with almost half of all cases occurring in the developing world (12, 13).

Lung cancer is generally divided into two types, small-cell and non-small-cell, although there are other, rarer types, such as carcinoid tumors. Small-cell lung cancer accounts for approximately 20 percent of all lung cancer cases and is almost exclusively caused by smoking. Non-small-cell lung cancer accounts for approximately 80 percent of all lung cancers and includes three subtypes: squamous-cell carcinoma (almost always caused by smoking), adenocarcinoma, and large-cell undifferentiated carcinoma. Recent decades have seen an increase in the frequency of adenocarcinoma and a decline in squamous-cell carcinoma in developed countries. This could be partly explained by an increase in the use of filtered cigarettes (14).

Lung cancer is frequently diagnosed at an incurable stage. Treatment for non-small-cell lung cancer (stages I, II, and occasionally IIIa) is based on surgery with adjuvant irradiation and/or chemotherapy. Patients with advanced non-small-cell lung cancer usually receive only chemotherapy. Surgery plays only a limited role in the management of small-cell lung cancer. Depending on the stage of disease and its complications, patients typically receive some combination of radiation and chemotherapy. Prognosis is poor in general, but it is considerably better in cases of non-small-cell lung cancer than in cases of small-cell lung cancer. For the approximately 70 percent of non-small-cell lung cancers that are unresectable, survival time varies greatly, from a few weeks to a few years, depending on the functional status of the patient at the time of diagnosis. In contrast, given its very aggressive nature, the median survival of patients with small-cell lung cancer is approximately 1 year (15).

Tobacco smoking is clearly the strongest risk factor for lung cancer, and despite its original description by Rottman (16) in 1898, smoking-induced lung cancer continues to be a major public health problem. In 2001, 856,000 of the annual trachea, bronchus, and lung cancer deaths (70 percent of the total number of such deaths) were attributable to smoking (17). The risk among smokers as compared with never smokers was increased 8–15 times in men and 2–10 times in women (18). Cessation of smoking is known to significantly reduce lung cancer risk, with the most marked effect being observed in heavy smokers, particularly among women (19). However, many persons who smoke continue to do so. Other risk factors for lung cancer include environmental tobacco smoke exposure, diet, and occupational exposures such as soot and asbestos (20).


   ASSOCIATIONS
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
In the last two decades, and especially in recent years, a large body of medical and epidemiologic literature has described genetic variants that appear to affect susceptibility to lung cancer. Multiple genes—including several in the GST group, cytochrome P-450 1A1 (CYP1A1) and several other genes in the cytochrome P-450 (CYP) group, microsomal epoxide hydrolase (mEH), aryl hydrocarbon receptor (AhR), NAD(P)H quinone oxidoreductase 1 (NQO1), myeloperoxidase (MPO), and N-acetyltransferase (NAT)—have been variably associated with the disease (14, 21–25). These effects are at least partly independent of the effects of tobacco; an excess risk of lung cancer has been observed in relatives of lung cancer patients regardless of smoking status (26, 27). While some of the familial risk could be due to environmental tobacco smoke exposure, a shared genetic risk is strongly suggested. Regardless, the independent effect on lung cancer risk is strongly amplified by cigarette smoking (17, 23, 28). Variants in several genes have now been shown to be associated with increased lung cancer risk specifically in smokers; smokers with the "at risk" genotype are at a significantly higher risk of lung cancer than smokers without the "at risk" genotype. Several general reviews of the topic are available (25, 29–33).

Seven meta-analyses and pooled analyses published to date have been consistent in finding a modest but statistically significant increase in risk for persons carrying the null variant (table 1); summary odds ratios from these meta-analyses range from 1.17 to 1.54. For the present review, we sought all population-based cohort, case-control, or cross-sectional studies reporting associations between the GSTM1 null variant and lung cancer. Cases had to be diagnosed with lung cancer, and controls had to be healthy or hospital-based controls without cancer. Full details on the methods used for collating and synthesizing data from these association studies are provided in the Appendix. Our literature search retrieved 2,597 papers published up to March 2006. We identified 98 studies for inclusion in the meta-analysis, and these are individually characterized in Web table 1 (http://aje.oxfordjournals.org/).

The 98 studies were undertaken in a wide range of ethnogeographic settings (Web table 1), with 46 percent (9,071 of 19,638) of cases being reported as Caucasian (data from 36 studies), 31 percent (6,088 of 19,638) of cases being reported as East Asian (data from 42 studies), and 23 percent (4,479 of 19,638) of cases being reported as of nonspecific ethnicity (included African-American, mixed ethnicity, and ethnicity not stated; data from 20 studies). Five studies accounted for just over one quarter of all cases (26 percent; 5,112 of 19,638). Forty-four studies used general population controls, 33 used hospital-based controls, and 21 used controls from other sources (included healthy workers, friends and spouses of cases, and source not stated). In several studies, investigators also reported results broken down by lung cancer clinical subtype, such as adenocarcinoma (40 studies), squamous-cell carcinoma (37 studies), small-cell carcinoma (22 studies), or large-cell carcinoma (7 studies).

Using a random-effects meta-analysis with a dominant genetic model, the combined odds ratio for lung cancer among persons with the GSTM1 null genotype was 1.22 (95 percent confidence interval (CI): 1.14, 1.30) (see Web figure 1, which is posted on the Journal's website (http://aje.oxfordjournals.org/)). The fixed-effect meta-analysis odds ratio for lung cancer was 1.16 (95 percent CI: 1.12, 1.21). There was some evidence of heterogeneity among these studies (I2 = 58 percent, 95 percent CI: 46, 66; p < 0.0001) and also of funnel plot asymmetry (Begg's test, p = 0.003). Ethnicity accounted for some of this heterogeneity (21 percent of the between-study variance, p < 0.001). Subgroup analyses were also undertaken (figure 1). When studies were subgrouped by ethnicity, the odds ratio for Caucasians was 1.04 (95 percent CI: 0.97, 1.11), with I2 equal to 22 percent (95 percent CI: 0, 48; p = 0.117), and the odds ratio for East Asians was 1.38 (95 percent CI: 1.24, 1.55), with I2 equal to 56 percent (95 percent CI: 34, 68; p < 0.0001). The odds ratios for general population and hospital-based control groups were 1.21 (95 percent CI: 1.10, 1.33) with I2 equal to 54 percent (95 percent CI: 31, 66; p < 0.0001) and 1.32 (95 percent CI: 1.14, 1.52) with I2 equal to 69 percent (95 percent CI: 54, 77; p < 0.0001), respectively. When only the large (>500 cases) studies were considered, the odds ratio for persons with the GSTM1 null genotype was 1.01 (95 percent CI: 0.91, 1.12), with I2 equal to 31 percent (95 percent CI: 0, 74; p = 0.216). Phenotyping rather than genotyping was conducted in five studies which, combined, gave an odds ratio of 1.63 (95 percent CI: 0.96, 2.74) with I2 equal to 75 percent (95 percent CI: 8.6, 88; p = 0.0028).


Figure 1
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  		FIGURE 1. Results from a random-effects meta-analysis of studies of glutathione S-transferase M1 (GSTM1) polymorphisms and lung cancer, according to various characteristics. OR, odds ratio; CI, confidence interval.

 
The combined odds ratio for adenocarcinoma cases (n = 4,005; 40 studies) was 1.18 (95 percent CI: 1.05, 1.32), with I2 equal to 48 percent (95 percent CI: 19, 63.3; p = 0.0005), for the GSTM1 null genotype. Small-cell carcinoma cases (n = 807; 22 studies) had an odds ratio of 1.35 (95 percent CI: 1.12, 1.64), with I2 equal to 31 percent (95 percent CI: 0, 58; p = 0.08). The combined odds ratio for squamous-cell carcinoma cases (n = 3,700; 37 studies) with the GSTM1 null genotype was 1.24 (95 percent CI: 1.10, 1.40), with I2 equal to 55 percent (95 percent CI: 30, 68; p < 0.0001). The large-cell carcinoma cases (n = 112; 7 studies) had an odds ratio of 1.06 (95 percent CI: 0.58, 1.93), with I2 equal to 50 percent (95 percent CI: 0, 77; p = 0.06).


   INTERACTIONS
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
Gene-gene interactions
An association between enzymes in either the CYP or GST families and a smoking-related cancer such as lung cancer is biologically plausible. Most toxic compounds are detoxified in two phases. In phase 1, atomic oxygen is introduced in a reaction catalyzed by the CYP gene family. This generates an oxygenated intermediate, which is a substrate for phase 2, in which several families of enzymes (including GST) add moieties that detoxify the substrate (34). With cigarette smoking, benzo[a]pyrene is considered a primary toxic byproduct, and it is metabolized by CYP1A1 to benzo[a]pyrene epoxide, which is the reactive intermediate. GSTM1 then converts this intermediate to benzo[a]pyrene-S-glutathione. As a result, either high CYP1A1 activity (conferred by the MspI "m2" variant of the CYP1A1 gene) or low GSTM1 activity (conferred by the null variant of the GSTM1 gene), or particularly their combination, will increase benzo[a]pyrene levels and therefore toxicity (35). Further mechanistic support is provided by research that correlates the GSTM1 null genotype with the DNA adducts (polycyclic aromatic hydrocarbon–deoxyguanosine monophosphate) that are known markers for carcinogenesis (36).

Few studies have investigated the role of gene-gene interactions in lung cancer, mainly because of the large numbers of participants that would be required to provide adequate statistical power. Nakachi et al. (37) found that persons with the CYP1A1 MspI or Ile/Val variant and persons with the GSTM1 null variant with low levels of cigarette smoking were at high risk of lung cancer, with odds ratios of 16.0 (95 percent CI: 3.76, 68.02) and 41.0 (95 percent CI: 8.68, 193.61), respectively. Although the evidence suggests that the risk of lung cancer is increased in carriers of both the GSTM1 null variant and the CYP1A1 variant, the wide confidence intervals obtained leave the results difficult to interpret (38–45). Studies investigating the interaction between the GSTM1 null variant and the glutathione S-transferase T1 (GSTT1) null variant have observed conflicting results, showing both reduced risk (42, 46) and increased risk (42, 44) of lung cancer for double null carriers.

Recently, Vineis et al. (47) conducted a pooled analysis through the GSEC (International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens) initiative (48), including six case-control studies with 611 lung cancer cases and 870 controls genotyped for GSTM1 null, GSTT1 null, and CYP1A1 MspI, Ile/Val, and Thr/Asn. Associations with lung cancer were observed in carriers of either CYP1A1 MspI, Ile/Val, or Thr/Asn and the double deletion of both GSTM1 and GSTT1. For the CYP1A1 Thr/Asn and double GSTM1 and GSTT1 deletion carriers, an odds ratio of 8.25 (95 percent CI: 2.29, 29.77) was observed. The gene-gene interaction between GSTM1 and CYP1A1, simplistically summarized here, is the topic of another registered HuGE review (49).

Gene-environment interactions
An increase in lung cancer risk is favored when the effect of increased smoking is assessed along with that of GSTM1 variation (50–53), but at least one study (54) has demonstrated an opposite effect, that is, an increased odds ratio at a lower level of smoking. The discrepancy may be based on the lack of consistent controls for concomitant polymorphisms (e.g., multiple variants of CYP and GST) other than the primary one (e.g., GSTM1) being tested for in an individual study. In theory, induction of some polymorphisms (e.g., CYP1A1 MspI) by cigarette smoke leads to increased carcinogen exposure, while induction of others leads to decreased carcinogen exposure. Studies controlling for all relevant polymorphisms have been lacking, making it difficult to fully assess interactions between smoking and genotype. Therefore, it is currently unknown whether any potentiating interaction is occurring. Stucker et al. (53) have argued that the GSTM1 null genotype and cigarette smoking are independent risk factors for lung cancer but are not synergistic. The interaction between GSTM1, smoking, and lung cancer has been registered as the topic of a separate HuGE review (49).

There are several dietary compounds and toxic exposures that will also need to be controlled for in order to fully elucidate gene-environment interactions related to lung cancer risk. The most notable of these are isothiocyanates, found in high concentrations in cruciferous vegetables. London et al. (55, 56) found a decreased risk (odds ratio (OR) = 0.36, 95 percent CI: 0.20, 0.63) associated with the GSTM1 null genotype when patients were stratified by urinary isothiocyanate level, and Spitz et al. (57) found increased risk in persons reporting lower isothiocyanate intake. Lewis et al. (58, 59) found decreased risk with higher consumption of cruciferous vegetables (OR = 0.27, 95 percent CI: 0.06, 1.33), but the wide confidence interval makes this finding inconclusive.

Other potentially significant interactions include use of smoky coal, which Lan et al. (60) found to confer increased risk in GSTM1-null subjects, and rural living, which conferred increased risk in one study (61). There have thus far been mixed data for an effect of vitamin C intake. Garcia-Closas et al. (62) found a protective effect, but London et al. (54) found no significant association between vitamin C intake and GSTM1 status for lung cancer risk. Both Woodson et al. (63) and London et al. (54) failed to find significantly altered odds ratios for lung cancer when a GSTM1-null population was stratified by β-carotene intake.


   LABORATORY TESTS
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
Molecular methods for determining GSTM1 genotype have been reviewed by Cotton et al. (9).


   POPULATION TESTING AND POTENTIAL HEALTH APPLICATIONS
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 
Given the uncertain positive predictive value of GSTM1 genetic testing as a predictor for lung cancer risk, the clinical value of such testing is questionable. From a public health perspective, an optimistic goal would be to use genetic testing to supplement current efforts to motivate people to stop smoking, but there are considerable obstacles to achieving this goal (64). The theory that knowledge of polymorphism-related lung cancer may somehow guide behavioral change (given the "voluntary" nature of smoking) has been tested by Audrain et al. (65) and Lerman et al. (66). They measured motivation to quit, ultimate quitting rates, and depressive symptoms in patients randomized to receive quit-smoking counseling, patients randomized to receive counseling plus biofeedback, and a third group in which genotype testing was added to these two methods. While persons who were told of their genetic predisposition to cancer experienced short-term positive gains in perceived risk, perceived quitting benefit, and fear arousal, cessation rates were not affected by genetic risk knowledge. Initially, the biomarker group experienced increased levels of depressive symptoms, but these were not maintained over 12 months. The authors suggested (65, 66) that genetic susceptibility information might prove more compelling to persons who received more intensive counseling and/or newer pharmacologic support (nicotine patches, etc.) than was provided in these studies.

In a subsequent study by McBride et al. (67), in which smokers were randomized to "usual care" or biofeedback (consisting of GST genetic testing and counseling), there was a greater prevalence of smoking abstinence in the biofeedback group at 6 months but not at 12 months (although a trend persisted at 12 months). Interestingly, the difference at 6 months was based generically on the biofeedback/counseling process; no difference was noted between persons told that they had the GSTM1-null genotype ("susceptible") and persons told that they were GST-normal ("not susceptible"). On the basis of these limited trials, there is no current justification for any population-based testing. However, this question will need to be revisited as gaps in our understanding of this issue are addressed through further research.


   CONCLUSIONS AND RECOMMENDATIONS FOR RESEARCH
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
APPENDIX
 References
 
In this paper, we have reviewed available evidence for the role of GSTM1 in predisposition to lung cancer. We conducted an updated meta-analysis of association studies involving a total of 19,638 cases and 25,266 controls from 98 studies, carefully avoiding the double-counting of participants in the analysis. The GSTM1 null variant was observed to be associated with a small increase in lung cancer risk (OR = 1.22, 95 percent CI: 1.14, 1.30), although no increased risk was apparent when only the five largest studies (>500 cases each) were considered (OR = 1.01, 95 percent CI: 0.91, 1.12). There was a suggestion that the GSTM1 null variant may confer increased risk in persons with an East Asian ethnic background (OR = 1.38, 95 percent CI: 1.24, 1.55), with a lack of convincing evidence for persons of Caucasian ethnicity (OR = 1.04, 95 percent CI: 0.97, 1.11). Although the studies that examined the relation of GSTM1 phenotype with lung cancer found a larger association (OR = 1.63, 95 percent CI: 0.96, 2.74), the confidence intervals were wide.

Several methodological issues should be considered in interpreting these findings. First, the key threat to literature-based reviews and meta-analyses is the possibility of reporting bias (the possibility that only the most exciting findings are available in the literature). We cannot rule out this possibility, not least because we observed a lack of association in the largest studies, which may be less prone to selective reporting. Second, higher levels of smoking may accentuate or minimize the effect of adverse genotypes on lung cancer risk. Tobacco smoking is the most firmly established risk factor for lung cancer (28, 68, 69). However, reporting of smoking exposure is not standardized, varies considerably across studies, and is difficult to address adequately in a review like this. Vineis et al. (70) have shown that the relation between lung cancer and smoking may level off at approximately 20 cigarettes per day. Third, polymorphism frequencies are known to vary by ethnicity (71), but the effect of this on risk has not yet been adequately studied. In the studies we identified, the frequencies of the GSTM1 null genotype among controls were similar in Caucasian and East Asian populations. The observed difference in the magnitude of the association between these populations does not appear to be explained by differences in genotype frequencies, suggesting more complex factors that warrant further investigation. Fourth, some studies have suggested that females may accumulate more adducts than males, even when smoking level and other confounding factors are controlled for (72). The clinical significance of this finding remains to be studied. When studies that reported results for females only (n = 6) and males only (n = 7) were subgrouped, odds ratios of 1.50 (95 percent CI: 1.06, 2.12) and 1.08 (95 percent CI: 0.91, 1.28), respectively, were observed for the GSTM1 null genotype and lung cancer (using a random-effects meta-analysis; data not otherwise shown).

It also appears that the effect of the GSTM1 genotype may vary according to histologic subtype. In our analyses, we evaluated the risk for each of the three major lung cancer subtypes. In spite of the variation in subtypes between studies, the odds ratios were elevated for squamous-cell carcinoma (OR = 1.23, 95 percent CI: 1.09, 1.39), small-cell carcinoma (OR = 1.33, 95 percent CI: 1.10, 1.60), and adenocarcinoma (OR = 1.13, 95 percent CI: 1.02, 1.25) when each type was considered independently. Our analyses indicated that previous meta-analyses have overestimated the effect of the GSTM1 null variant on each of the three main histologic subtypes (table 1). This is an area in which more research is warranted.

In addition to these questions, contributions from other gene variants may also be responsible for differences between studies. For example, genetic polymorphisms in the CYP family may modulate nicotine metabolism (73) or its effects on dopamine receptors (66) and therefore addiction. Possible interaction between GSTM1 and these CYP genotypes, and other polymorphisms theorized to modulate lung cancer risk, were infrequently investigated and rarely accounted for in the studies outlined in Web table 1. Bartsch et al. (74) have suggested that the interactions result in a greater-than-additive risk. These effect-modifying interactions were not taken into account in our analyses of the association between lung cancer and GSTM1 genotype. Realistically, however, comprehensive studies of genetic and environmental factors contributing to lung cancer may not be feasible until chip array technology allows for ready characterization of multiple relevant genes. Furthermore, making use of such technology when it becomes available will require large study samples in order to generate sufficient power to evaluate multiple potential contributors to risk. Researchers will need to consider the ability of the latest technology to address these concerns.

Because of the complex pathways of carcinogen metabolism and the various enzymes involved, any single gene might play a smaller, more limited role in the risk of lung cancer. In this review, we observed a modest effect of the GSTM1 null variant on lung cancer risk, and we would therefore encourage much larger studies than have traditionally been conducted in this area. Larger, more comprehensive studies would allow for meaningful stratification and allow stronger conclusions to be drawn regarding the effects of study characteristics such as ethnicity or histologic subtype. Larger studies would also permit evaluation of gene-gene and gene-environment interactions, factors that are clearly important in complex diseases such as lung cancer. In the process of exploring such research, it is imperative to use foresight in targeting it towards clear applicability to public health (64).

Editor's note: References 89–228 are cited in Web table 1, which is posted on the Journal's website (http://aje.oxfordjournals.org/).


   APPENDIX
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
References
 
Selection criteria and identification of studies
We sought all population-based cohort, case-control, and cross-sectional studies reporting associations between the GSTM1 null variant and lung cancer. Cases had to be diagnosed with lung cancer, and controls had to be healthy or hospital-based controls without cancer. Electronic searches, not limited to the English language, were performed using MEDLINE, EMBASE, BIOSIS, and the Science Citation Index, and we also perused the reference lists of retrieved articles and previous meta-analyses. The latest searches were undertaken on March 13 and 14, 2006. The MEDLINE search strategy, using PubMed Medical Subject Headings (MeSH), for assessing the association between the GSTM1 null variant and lung cancer was the following: (glutathione S-transferase* or glutathione S transferase* or glutathione transferase[MeSH] or GSTM1 or aryl hydrocarbon hydroxylases[MeSH]) and (lung or respiratory tract or lung[MeSH] or cancer* or neoplasm* or neoplasms[MeSH] or carcino* or carcinoma[MeSH] or tumour* or tumor* or tumour[MeSH] or DNA adduct* or DNA adducts[MeSH] or squamous cell carcinoma* or large-cell carcinoma* or small cell carcinoma* or adenocarcinoma* or non-small cell carcinoma* or lung neoplasms[MeSH] or respiratory tract neoplasms[MeSH]). Two reviewers (C. C. and G. S. S.) scanned relevant articles identified by the search independently on the basis of title, keywords, and abstract (where available) and rejected on an initial screen any article that clearly did not meet the inclusion criteria. The full text of all remaining articles was obtained for further evaluation by the same two reviewers. In the case of uncertainty about eligibility, a third reviewer (A. J. F.) was consulted before a decision was made.

Data collection and analysis
Data were extracted independently by two reviewers (A. J. F. and G. S. S.), using a prepiloted data extraction form (with any discrepancies being resolved by discussion). Variables on which information was collected were study design; geographic location; genotype frequencies, by categorical disease outcome (including clinical subtypes if presented); mean ages of cases and controls; proportions of males and persons in ethnic subgroups (defined as European continental ancestry, East Asian ancestry, or other, including African-American); genotyping method used; and blinding of laboratory workers to participant case-control status. Where multiple publications on the same study were identified, data were extracted from each article and the most complete and up-to-date information was identified. Studies that presented results for different ethnic groups or different control sources were considered as a single study for the overall analysis but were considered as individual studies for the ethnicity and control-source subanalyses, in order to avoid double-counting of individuals.

Primary analyses were conducted using a dominant inheritance model. Meta-analyses used a standard approach, weighting by precision and incorporating random effects to allow for the variation in true associations across studies. Funnel plots were used to assess assumptions involved in meta-analysis and to explore the relation between precision and magnitude of association. Consistency of the gene effect sizes across studies was assessed using the I2 statistic, which describes the percentage of total variation in point estimates attributable to genuine variation rather than sampling error (75). Variation was further explored by prespecified subgrouping of studies according to sample size (<100, 100–499, or ≥500 cases), ethnicity (Caucasian, East Asian, other), source of controls (general population, hospital-based, other), study design (retrospective, prospective), and blinding of genotype to disease outcome (yes, no, unknown). Sensitivity analyses were also conducted by performing fixed-effect meta-analyses. All ranges presented are 95 percent confidence intervals unless otherwise specified.


   ACKNOWLEDGMENTS
 
This review was supported by the University of Washington's Center for Ecogenetics and Environmental Health, via US National Institute of Environmental Health Sciences grant P30ES07033. Aspects of this work were supported by funding from the United Kingdom Department of Health and the United Kingdom Department of Trade and Industry held under the program of the Cambridge Genetics Knowledge Park. G. S. S., A. J. F., and J. P. T. H. were supported by a research grant from the PHG Foundation (Cambridge, United Kingdom) held by the United Kingdom Medical Research Council.

The authors thank Dr. Zheng Ye for allowing access to previously extracted data from the Chinese literature and Dr. Karen Edwards for a review of the manuscript.

Drs. C. Carlsten and G. S. Sagoo contributed equally to this article.

Conflict of interest: none declared.


   NOTES
 
Editor's note: This article also appears on the website of the Human Genome Epidemiology Network (http://www.cdc.gov/genomics/hugenet/).


   References
TOP
 ABSTRACT
 INTRODUCTION
 GENE VARIANTS
 GENE VARIANT FREQUENCY
 DISEASE
 ASSOCIATIONS
 INTERACTIONS
 LABORATORY TESTS
 POPULATION TESTING AND POTENTIAL...
 CONCLUSIONS AND RECOMMENDATIONS...
 APPENDIX
 References
 

  1. Seidegård J, Pero RW, Miller DG, et al. A glutathione transferase in human leukocytes as a marker for the susceptibility to lung cancer. Carcinogenesis (1986) 7:751–3.[Abstract/Free Full Text]
  2. The Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions 4.2.5 (updated May 2005). (2007) London, United Kingdom: John Wiley and Sons Ltd. (http://www.cochrane.dk/cochrane/handbook/hbook.htm).
  3. Little J, Higgins JPT, eds. The HuGENetTM HuGE review handbook, version 1.0. (2007) Ottawa, Ontario, Canada: HuGENet Canada Coordinating Centre. (http://www.hugenet.ca/).
  4. International Union of Biochemistry and Molecular Biology. EC 2.5.1.18. In: IUBMB Enzyme Nomenclature. (Database). London, United Kingdom: Department of Chemistry, Queen Mary, University of London, 2007. (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/5/1/18.html).
  5. Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol (1995) 30:445–600.[Web of Science][Medline]
  6. Glutathione S-transferase, mu-1; GSTM1. In: OMIM: Online Mendelian Inheritance in Man. (Database). Bethesda, MD: National Center for Biotechnology Information, National Institutes of Health, 2007. (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=138350).
  7. Hengstler JG, Arand M, Herrero ME, et al. Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility. Recent Results Cancer Res (1998) 154:47–85.[Medline]
  8. Rebbeck TR. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev (1997) 6:733–43.[Abstract/Free Full Text]
  9. Cotton SC, Sharp L, Little J, et al. Glutathione S-transferase polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol (2000) 151:7–32.[Abstract/Free Full Text]
  10. Zhong S, Howie AF, Ketterer B, et al. Glutathione-S-transferase mu locus: use of genotyping and phenotyping assays to assess association with lung cancer susceptibility. Carcinogenesis (1991) 12:1533–7.[Abstract/Free Full Text]
  11. Geisler SA, Olshan AF. GSTM1, GSTT1, and the risk of squamous cell carcinoma of the head and neck: a mini-HuGE review. Am J Epidemiol (2001) 154:95–105.[Abstract/Free Full Text]
  12. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin (2005) 55:74–108.[Abstract/Free Full Text]
  13. Devesa SS, Bray F, Vizcaino AP, et al. International lung cancer trends by histologic type: male:female differences diminishing and adenocarcinoma rates rising. Int J Cancer (2005) 117:294–9.[CrossRef][Web of Science][Medline]
  14. Kiyohara C, Yoshimasu K, Takayama K, et al. NQO1, MPO, and the risk of lung cancer: a HuGE review. Genet Med (2005) 7:463–78.[Web of Science][Medline]
  15. Tamura T. New state of the art in small-cell lung cancer. Oncology (Williston Park) (2001) 15:8–10.[Medline]
  16. Rottman H. Uber primare lungencarcinoma. (In German). (Inaugural dissertation). (1898) Würzburg, Germany: University of Würzburg.
  17. Danaei G, Vander HS, Lopez AD, et al. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet (2005) 366:1784–93.[CrossRef][Web of Science][Medline]
  18. Stewart BW, Kleihues P, eds. Lung cancer. In: World cancer report (2003) Lyon, France: IARC Press. 182–7.
  19. Khuder SA, Mutgi AB. Effect of smoking cessation on major histologic types of lung cancer. Chest (2001) 120:1577–83.[CrossRef][Web of Science][Medline]
  20. Alberg AJ, Ford JG, Samet JM. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines. Chest (2007) 132, 2nd ed. (suppl):29S–55S.[CrossRef][Web of Science][Medline]
  21. Kiyohara C, Yoshimasu K, Takayama K, et al. EPHX1 polymorphisms and the risk of lung cancer: a HuGE review. Epidemiology (2006) 17:89–99.[CrossRef][Web of Science][Medline]
  22. Raimondi S, Paracchini V, Autrup H, et al. Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review. Am J Epidemiol (2006) 164:1027–42.[Abstract/Free Full Text]
  23. Sasco AJ, Secretan MB, Straif K. Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer (2004) 45(suppl 2):S3–9.
  24. Taioli E, Benhamou S, Bouchardy C, et al. Myeloperoxidase G-463A polymorphism and lung cancer: a HuGE Genetic Susceptibility to Environmental Carcinogens pooled analysis. Genet Med (2007) 9:67–73.[Web of Science][Medline]
  25. Benhamou S, Sarasin A. ERCC2/XPD gene polymorphisms and lung cancer: a HuGE review. Am J Epidemiol (2005) 161:1–14.[Abstract/Free Full Text]
  26. Ooi WL, Elston RC, Chen VW, et al. Increased familial risk for lung cancer. J Natl Cancer Inst (1986) 76:217–22.[Web of Science][Medline]
  27. Sellers TA, Ooi WL, Elston RC, et al. Increased familial risk for non-lung cancer among relatives of lung cancer patients. Am J Epidemiol (1987) 126:237–46.[Abstract/Free Full Text]
  28. Wakai K, Inoue M, Mizoue T, et al. Tobacco smoking and lung cancer risk: an evaluation based on a systematic review of epidemiological evidence among the Japanese population. Jpn J Clin Oncol (2006) 36:309–24.[Abstract/Free Full Text]
  29. Bouchardy C, Benhamou S, Jourenkova N, et al. Metabolic genetic polymorphisms and susceptibility to lung cancer. Lung Cancer (2001) 32:109–12.[CrossRef][Web of Science][Medline]
  30. Mucci LA, Wedren S, Tamimi RM, et al. The role of gene-environment interaction in the aetiology of human cancer: examples from cancers of the large bowel, lung and breast. J Intern Med (2001) 249:477–93.[CrossRef][Web of Science][Medline]
  31. Christiani DC. Smoking and the molecular epidemiology of lung cancer. Clin Chest Med (2000) 21:87–93. viii.[CrossRef][Web of Science][Medline]
  32. Shields PG, Harris CC. Cancer risk and low-penetrance susceptibility genes in gene-environment interactions. J Clin Oncol (2000) 18:2309–15.[Abstract/Free Full Text]
  33. Haugen A, Ryberg D, Mollerup S, et al. Gene-environment interactions in human lung cancer. Toxicol Lett (2000) 112:233–7.[CrossRef][Web of Science][Medline]
  34. Nebert DW, McKinnon RA, Puga A. Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol (1996) 15:273–80.[Web of Science][Medline]
  35. Vineis P, Malats N, Lang M, et al. Metabolic polymorphisms and susceptibility to cancer. (1999) Lyon, France: International Agency for Research on Cancer. (IARC Scientific Publication no. 148).
  36. Kato S, Bowman ED, Harrington AM, et al. Human lung carcinogen-DNA adduct levels mediated by genetic polymorphisms in vivo. J Natl Cancer Inst (1995) 87:902–7.[Abstract/Free Full Text]
  37. Nakachi K, Imai K, Hayashi S, et al. 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) 53:2994–9.[Abstract/Free Full Text]
  38. Chen S, Xue K, Xu L, et al. Polymorphisms of the CYP1A1 and GSTM1 genes in relation to individual susceptibility to lung carcinoma in Chinese population. Mutat Res (2001) 458:41–7.[Medline]
  39. Dialyna IA, Miyakis S, Georgatou N, et al. Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk. Oncol Rep (2003) 10:1829–35.[Web of Science][Medline]
  40. Dresler CM, Fratelli C, Babb J, et al. Gender differences in genetic susceptibility for lung cancer. Lung Cancer (2000) 30:153–60.[CrossRef][Web of Science][Medline]
  41. Hong YS, Chang JH, Kwon OJ, et al. Polymorphism of the CYP1A1 and glutathione-S-transferase genes in Korean lung cancer patients. Exp Mol Med (1998) 30:192–8.[Web of Science][Medline]
  42. Imyanitov EN, Belogubova EV, Karpova MB, et al. Reassessment of GSTM1 and GSTT1 cancer predisposing roles: comparison of genotypes in elderly tumour-free smokers and non-smokers vs. healthy donors vs. lung cancer patients. (Abstract). Int J Cancer Suppl (2002) 13:421.
  43. Persson I, Johansson I, Lou YC, et al. Genetic polymorphism of xenobiotic metabolizing enzymes among Chinese lung cancer patients. Int J Cancer (1999) 81:325–9.[CrossRef][Web of Science][Medline]
  44. Sreeja L, Syamala V, Hariharan S, et al. Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population. J Hum Genet (2005) 50:618–27.[CrossRef][Web of Science][Medline]
  45. Zhang L, Wang X, Hao X, et al. Relationship between susceptibility to lung cancer and genetic polymorphism in P4501A1, GSTM1. J Clin Oncol (2002) 29:536–40.
  46. London SJ, Yu MC, Yuan JM, et al. Lung cancer risk and polymorphisms of GSTM1, GSTT1 and CYP1A1 in serum DNA from a cohort of Shanghai men. In: Proceedings of the annual meeting of the American Association for Cancer Research, vol 40. (1999) Philadelphia, PA: American Association for Cancer Research. 249.
  47. Vineis P, Anttila S, Benhamou S, et al. Evidence of gene gene interactions in lung carcinogenesis in a large pooled analysis. Carcinogenesis (2007) 28:1902–5.[Abstract/Free Full Text]
  48. Taioli E. International collaborative study on genetic susceptibility to environmental carcinogens. Cancer Epidemiol Biomarkers Prev (1999) 8:727–8.[Free Full Text]
  49. Sagoo G, Higgins J. GSTM1, CYP1A1 and smoking and lung cancer. In: HuGE Reviews—reviews in preparation. (Registry). (2007) Atlanta, GA: National Office of Public Health Genomics, Centers for Disease Control and Prevention. (http://www.cdc.gov/genomics/hugenet/reviews_prep.htm#Cancer).
  50. Ford JG, Li YL, O'Sullivan MM, et al. Glutathione S-transferase M1 polymorphism and lung cancer risk in African-Americans. Carcinogenesis (2000) 21:1971–5.[Abstract/Free Full Text]
  51. Jourenkova-Mironova N, Wikman H, Bouchardy C, 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.[Web of Science][Medline]
  52. Kihara M, Kihara M, Noda K. Lung cancer risk of GSTM1 null genotype is dependent on the extent of tobacco smoke exposure. Carcinogenesis (1994) 15:415–18.[Abstract/Free Full Text]
  53. Stucker I, de Waziers I, Cenee S, et al. GSTM1, smoking and lung cancer: a case-control study. Int J Epidemiol (1999) 28:829–35.[Abstract/Free Full Text]
  54. London SJ, Daly AK, Cooper J, 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) 87:1246–53.[Abstract/Free Full Text]
  55. London SJ, Yuan JM, Chung FL, et al. Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China. Lancet (2000) 356:724–9.[CrossRef][Web of Science][Medline]
  56. London SJ. Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China. (Erratum). Lancet (2000) 356:2104.[Web of Science][Medline]
  57. Spitz MR, Duphorne CM, Detry MA, 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) 9:1017–20.[Abstract/Free Full Text]
  58. Lewis S, Brennan P, Nyberg F, et al. Re: Spitz [et al.]. Dietary intake of isothiocyanates: evidence of a joint effect with glutathione S-transferase polymorphisms in lung cancer risk. (Letter). Cancer Epidemiol Biomarkers Prev (2001) 10:1105–6.[Free Full Text]
  59. Lewis S, Brennan P, Nyberg F, et al. Cruciferous vegetable intake, GSTM1 genotype and lung cancer risk in a non-smoking population. IARC Sci Publ (2002) 156:507–8.[Medline]
  60. Lan Q, He XZ, Costa DJ, 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) 9:605–8.[Abstract/Free Full Text]
  61. Malats N, Camus-Radon AM, Nyberg F, et al. Lung cancer risk in nonsmokers and GSTM1 and GSTT1 genetic polymorphism. Cancer Epidemiol Biomarkers Prev (2000) 9:827–33.[Abstract/Free Full Text]
  62. Garcia-Closas M, Kelsey KT, Wiencke JK, 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) 8:544–53.[CrossRef][Web of Science][Medline]
  63. Woodson K, Stewart C, Barrett M, et al. Effect of vitamin intervention on the relationship between GSTM1, smoking, and lung cancer risk among male smokers. Cancer Epidemiol Biomarkers Prev (1999) 8:965–70.[Abstract/Free Full Text]
  64. Carlsten C, Burke W. Potential for genetics to promote public health: genetics research on smoking suggests caution about expectations. JAMA (2006) 296:2480–2.[Free Full Text]
  65. Audrain J, Boyd NR, Roth J, et al. Genetic susceptibility testing in smoking-cessation treatment: one-year outcomes of a randomized trial. Addict Behav (1997) 22:741–51.[CrossRef][Web of Science][Medline]
  66. Lerman C, Caporaso N, Main D, et al. Depression and self-medication with nicotine: the modifying influence of the dopamine D4 receptor gene. Health Psychol (1998) 17:56–62.[CrossRef][Web of Science][Medline]
  67. McBride CM, Bepler G, Lipkus IM, et al. Incorporating genetic susceptibility feedback into a smoking cessation program for African-American smokers with low income. Cancer Epidemiol Biomarkers Prev (2002) 11:521–8.[Abstract/Free Full Text]
  68. Gandini S, Botteri E, Iodice S, et al. Tobacco smoking and cancer: a meta-analysis. Int J Cancer (2008) 122:155–64.[CrossRef][Web of Science][Medline]
  69. Zhong L, Goldberg MS, Parent ME, et al. Exposure to environmental tobacco smoke and the risk of lung cancer: a meta-analysis. Lung Cancer (2000) 27:3–18.[CrossRef][Web of Science][Medline]
  70. Vineis P, Kogevinas M, Simonato L, et al. Levelling-off of the risk of lung and bladder cancer in heavy smokers: an analysis based on multicentric case-control studies and a metabolic interpretation. Mutat Res (2000) 463:103–10.[CrossRef][Web of Science][Medline]
  71. Kelsey KT, Spitz MR, Zuo ZF, et al. 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) 8:554–9.[CrossRef][Web of Science][Medline]
  72. Ryberg D, Hewer A, Phillips DH, et al. Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients. Cancer Res (1994) 54:5801–3.[Abstract/Free Full Text]
  73. Tyndale RF, Pianezza ML, Sellers EM. A common genetic defect in nicotine metabolism decreases risk for dependence and lowers cigarette consumption. Nicotine Tob Res (1999) 1(suppl 2):S63–7.[Abstract/Free Full Text]
  74. Bartsch H, Nair U, Risch A, et al. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers. Cancer Epidemiol Biomarkers Prev (2000) 9:3–28.[Abstract/Free Full Text]
  75. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ (2003) 327:557–60.[Free Full Text]
  76. McWilliams JE, Sanderson BJS, Harris EL, et al. Glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk. Cancer Epidemiol Biomarkers Prev (1995) 4:589–94.[Abstract]
  77. d'Errico A, Taioli E, Chen X, et al. Genetic metabolic polymorphisms and the risk of cancer: a review of the literature. Biomarkers (1996) 1:149–73.[CrossRef][Web of Science]
  78. Houlston RS. Glutathione S-transferase M1 status and lung cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev (1999) 8:675–82.[Abstract/Free Full Text]
  79. d'Errico A, Malats N, Vineis P, et al. Review of studies of selected metabolic polymorphisms and cancer. IARC Sci Publ (1999) 148:323–93.[Medline]
  80. Skuladottir H, Autrup H, Autrup J, et al. Polymorphisms in genes involved in xenobiotic metabolism and lung cancer risk under the age of 60 years—a pooled study of lung cancer patients in Denmark and Norway. Lung Cancer (2005) 48:187–99.[CrossRef][Web of Science][Medline]
  81. Ye Z, Song H, Higgins JP, et al. Five glutathione S-transferase gene variants in 23,452 cases of lung cancer and 30,397 controls: meta-analysis of 130 studies. PLoS Med (2006) 3:e91. (Electronic article).[CrossRef][Medline]
  82. Shi X, Zhou S, Wang Z, et al. CYP1A1 and GSTM1 polymorphisms and lung cancer risk in Chinese populations: a meta-analysis. Lung Cancer (2007) Sep 25 [Epub ahead of print].
  83. Stucker I, Boffetta P, Antilla S, et al. Lack of interaction between asbestos exposure and glutathione S-transferase M1 and T1 genotypes in lung carcinogenesis. Cancer Epidemiol Biomarkers Prev (2001) 10:1253–8.[Abstract/Free Full Text]
  84. Benhamou S, Lee WJ, Alexandrie AK, et al. Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk. Carcinogenesis (2002) 23:1343–50.[Abstract/Free Full Text]
  85. Benhamou S, Lee WJ, Alexandrie AK, et al. Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk. (Erratum). Carcinogenesis (2002) 23:1771.[Free Full Text]
  86. Hung RJ, Boffetta P, Brockmoller J, et al. CYP1A1 and GSTM1 genetic polymorphisms and lung cancer risk in Caucasian non-smokers: a pooled analysis. Carcinogenesis (2003) 24:875–82.[Abstract/Free Full Text]
  87. Vineis P, Veglia F, Anttila S, et al. CYP1A1, GSTM1 and GSTT1 polymorphisms and lung cancer: a pooled analysis of gene-gene interactions. Biomarkers (2004) 9:298–305.[CrossRef][Web of Science][Medline]
  88. Raimondi S, Boffetta P, Anttila S, et al. Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study. Mutat Res (2005) 592:45–57.[Web of Science][Medline]
  89. Adonis M, Martínez V, Marín P, et al. Smoking habit and genetic factors associated with lung cancer in a population highly exposed to arsenic. Toxicol Lett (2005) 159:32–7.[CrossRef][Web of Science][Medline]
  90. Adonis M, Martinez V, Marin P, et al. CYP1A1 and GSTM1 genetic polymorphisms in lung cancer populations exposed to arsenic in drinking water. Xenobiotica (2005) 35:519–30.[CrossRef][Web of Science][Medline]
  91. Alexandrie AK, Sundberg MI, Seidegård J, et al. 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) 15:1785–90.[Abstract/Free Full Text]
  92. Alexandrie AK, Nyberg F, Warholm M, et al. 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) 13:908–14.[Abstract/Free Full Text]
  93. Aras S, Baltaci V, Yildirim O, et al. Glutathione S-transferase M1 and T1 gene polymorphism in patients with lung cancer among Turkish population. Biotechnol Biotech Equip (2001) 15:54–61.
  94. Barnholtz-Sloan JS, Chakraborty R, Sellers TA, et al. Examining population stratification via individual ancestry estimates versus self-reported race. Cancer Epidemiol Biomarkers Prev (2005) 14:1545–51.[Abstract/Free Full Text]
  95. Brennan P, Hsu CC, Moullan N, et al. Effect of cruciferous vegetables on lung cancer in patients stratified by genetic status: a mendelian randomisation approach. Lancet (2005) 366:1558–60.[CrossRef][Web of Science][Medline]
  96. Brockmöller J, Kerb R, Drakoulis N, et al. Genotype and phenotype of glutathione S-transferase class mu isoenzymes mu and psi in lung cancer patients and controls. Cancer Res (1993) 53:1004–11.[Abstract/Free Full Text]
  97. Butkiewicz D, Cole KJ, Phillips DH, et al. 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) 8:315–23.[Web of Science][Medline]
  98. Cantlay AM, Smith CAD, Wallace WA, et al. Heterogeneous expression and polymorphic genotype of glutathione S-transferases in human lung. Thorax (1994) 49:1010–14.[Abstract/Free Full Text]
  99. 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 Sci Res (2004) 8:126–32.
  100. Cerrahoglu K, Kunter E, Isitmangil T, et al. Can't lung cancer patients detoxify procarcinogens? Allerg Immunol (Paris) (2002) 34:51–5.[Medline]
  101. Chan Y, Wang X, Wang X, et al. A study of genetic polymorphism of GSTM1 gene in normal population and lung cancer population in Yunnan. J Yunnan Norm Univ (2002) 22:52–4.
  102. Chan EC, Lam SY, Fu KH, et al. Polymorphisms of the GSTM1, GSTP1, MPO, XRCC1, and NQO1 genes in Chinese patients with non-small cell lung cancers: relationship with aberrant promoter methylation of the CDKN2A and RARB genes. Cancer Genet Cytogenet (2005) 162:10–20.[CrossRef][Web of Science][Medline]
  103. Chan-Yeung M, Tan-Un KC, Ip MSM, et al. Lung cancer susceptibility and polymorphisms of glutathione-S-transferase genes in Hong Kong. Lung Cancer (2004) 45:155–60.[CrossRef][Web of Science][Medline]
  104. Xue K, Xu L, Chen S, et al. Polymorphisms of the CYP1A1 and GSTM1 genes and their combined effects on individual susceptibility to lung cancer in a Chinese population. (In Chinese). Zhonghua Yi Xue Yi Chuan Xue Za Zhi (2001) 18:125–7.[Medline]
  105. Chou YC, Wu MH, Wu CC, et al. Total urinary isothiocyanates, glutathione S-transferase M1 genotypes, and lung cancer risk: a preliminary nested case-control study in Taiwan. J Med Sci (2005) 25:21–5.
  106. Deakin M, Elder J, Hendrickse C, 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) 17:881–4.[Abstract/Free Full Text]
  107. Dong C, Yang Q, Jiang B, et al. Study on the relationship between polymorphisms of CYP1A1 gene and susceptibility of lung cancer in Sichuan population. (In Chinese). Chin J Lung Cancer (2004) 7–38. 42.
  108. Dziadziuszko R, Szymanowska A, Jassem E, et al. Combined analysis of P53 Arg72Pro, GSTM1 and GSTT1 gene polymorphisms as predisposing factors for non-small cell lung cancer (NSCLC) development. (Abstract). J Clin Oncol (2005) 23(suppl):856S.
  109. Gao Y, Zhang Q. Polymorphisms of the GSTM1 and CYP2D6 genes associated with susceptibility to lung cancer in Chinese. Mutat Res (1999) 444:441–9.[Web of Science][Medline]
  110. Gao Y, Zhang Q. Polymorphisms of the GSTM1 and CYP2D6 genes associated with susceptibility to lung cancer in Chinese. (Erratum). Mutat Res (2000) 464:311.[Web of Science]
  111. Gaspar P, Moreira J, Kvitko K, et al. CYP1A1, CYP2E1, GSTM1, GSTT1, GSTP1, and TP53 polymorphisms: do they indicate susceptibility to chronic obstructive pulmonary disease and non-small-cell lung cancer? Genet Mol Biol (2004) 27:133–8.
  112. Ge H, Lam WK, Lee J, et al. Analysis of L-myc and GSTM1 genotypes in Chinese non-small cell lung carcinoma patients. Lung Cancer (1996) 15:355–66.[CrossRef][Web of Science][Medline]
  113. Gsur A, Haidinger G, Hohenstein K, et al. Genetic polymorphisms of cytochrome P4501A1 and glutathione S-transferase M1: a lung cancer case control study. (Abstract). Eur J Cancer (1999) 35(suppl):S250.
  114. Gsur A, Haidinger G, Hollaus P, et al. Genetic polymorphisms of CYP1A1 and GSTM1 and lung cancer risk. Anticancer Res (2001) 21:2237–42.[Web of Science][Medline]
  115. Habalova V, Salagovic J, Kalina I, et al. Combined analysis of polymorphisms in glutathione S-transferase M1 and microsomal epoxide hydrolase in lung cancer patients. Neoplasma (2004) 51:352–7.[Web of Science][Medline]
  116. Harris MJ, Coggan M, Langton L, et al. Polymorphism of the pi class glutathione S-transferase in normal populations and cancer patients. Pharmacogenetics (1998) 8:27–31.[CrossRef][Web of Science][Medline]
  117. Harrison DJ, Cantlay AM, Rae F, et al. Frequency of glutathione S-transferase M1 deletion in smokers with emphysema and lung cancer. Hum Exp Toxicol (1997) 16:356–60.[Abstract/Free Full Text]
  118. Heckbert SR, Weiss NS, Hornung SK, et al. 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) 84:414–22.[Abstract/Free Full Text]
  119. Hirvonen A, Husgafvel-Pursiainen K, Anttila S, et al. The GSTM1 null genotype as a potential risk modifier for squamous-cell carcinoma of the lung. Carcinogenesis (1993) 14:1479–81.[Abstract/Free Full Text]
  120. Hirvonen A, Husgafvel-Pursiainen K, Anttila S, et al. Metabolic cytochrome P450 genotypes and assessment of individual susceptibility to lung cancer. Pharmacogenetics (1992) 2:259–63.[CrossRef][Web of Science][Medline]
  121. Hirvonen A, Husgafvel-Pursiainen K, Karjalainen A, et al. Point-mutational MspI and Ile-Val polymorphisms closely linked in the CYP1A1 gene: lack of association with susceptibility to lung cancer in a Finnish study population. Cancer Epidemiol Biomarkers Prev (1992) 1:485–9.[Abstract]
  122. Hirvonen A, Husgafvel-Pursiainen K, Anttila S, et al. Polymorphism in CYP1A1 and CYP2D6 genes: possible association with susceptibility to lung cancer. Environ Health Perspect (1993) 101(suppl 3):109–12.
  123. Hirvonen A, Bouchardy C, Mitrunen K, et al. Polymorphic GSTs and cancer predisposition. Chem-Biol Interact (2001) 133:75–80.[Web of Science]
  124. Nakajima T, Elovaara E, Anttila S, et al. Expression and polymorphism of glutathione S-transferase in human lungs: risk factors in smoking-related lung cancer. Carcinogenesis (1995) 16:707–11.[Abstract/Free Full Text]
  125. Saarikoski ST, Voho A, Reinikainen M, et al. Combined effect of polymorphic GST genes on individual susceptibility to lung cancer. Int J Cancer (1998) 77:516–21.[CrossRef][Web of Science][Medline]
  126. Ryberg D, Skaug V, Hewer A, et al. Genotypes of glutathione transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk. Carcinogenesis (1997) 18:1285–9.[Abstract/Free Full Text]
  127. Hou SM, Ryberg D, Falt S, et al. GSTM1 and NAT2 polymorphisms in operable and non-operable lung cancer patients. Carcinogenesis (2000) 21:49–54.[Abstract/Free Full Text]
  128. Autrup H. Susceptibility to lung cancer. (Abstract). Eur J Cancer Clin Oncol (1987) 23:1731.
  129. Ryberg D, Skaug V, Hewer A, et al. Combined genotypes of glutathione S-transferase M1 and P1 and their significance for lung DNA adduct levels and cancer risk. In: Proceedings of the annual meeting of the American Association for Cancer Research, vol 38. (1997) Philadelphia, PA: American Association for Cancer Research. 618.
  130. Tefre T, Ryberg D, Haugen A, et al. Human CYP1A1 (cytochrome P(1)450) gene: lack of association between the Msp I restriction fragment length polymorphism and incidence of lung cancer in a Norwegian population. Pharmacogenetics (1991) 1:20–5.[CrossRef][Medline]
  131. Hu Y, Gao Y, Zhang Q. Genetic polymorphisms of CYP1A1, 2D6, and GSTM1 related with susceptibility to lung cancer. Tumor (Shanghai) (1998) 18:269–71.
  132. Belogubova EV, Togo AV, Kondrat'eva TV, et al. Polymorphism of the GSTM1 gene in lung cancer resistance and susceptibility. Vopr Onkol (2000) 46:549–54.[Medline]
  133. Belogubova EV, Togo AV, Kondratieva TV, et al. GSTM1 genotypes in elderly tumour-free smokers and non-smokers. Lung Cancer (2000) 29:189–95.[Web of Science][Medline]
  134. Belogubova EV, Togo AV, Karpova MB, 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) 43:259–66.[CrossRef][Web of Science][Medline]
  135. Belogubova EV, Ulibina YM, Suvorova IK, et al. Combined CYP1A1/GSTM1 at-risk genotypes are overrepresented in squamous cell lung carcinoma patients but underrepresented in elderly tumor-free subjects. J Cancer Res Clin Oncol (2006) 132:327–31.[CrossRef][Web of Science][Medline]
  136. Jang SS, Jung CY, Lee SY, et al. The GSTT1 genotype as a marker for susceptibility to lung cancer in Korean female never smokers. Tuberc Respir Dis (2003) 54:485–94.
  137. 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) 83:866–70.[Web of Science]
  138. Goto I, Yoneda S, Yamamoto M, et al. Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer. Cancer Res (1996) 56:3725–30.[Abstract/Free Full Text]
  139. Kawajiri K, Nakachi K, Imai K, et al. Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer. Carcinogenesis (1993) 14:1085–9.[Abstract/Free Full Text]
  140. Kawajiri K, Watanabe J, Eguchi H, et al. Genetic polymorphisms of drug-metabolizing enzymes and lung cancer susceptibility. Pharmacogenetics (1995) 5. (spec. no.):S70–3.
  141. Kawajiri K, Eguchi H, Nakachi K, et al. Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer. Cancer Res (1996) 56:72–6.[Abstract/Free Full Text]
  142. Kihara M, Kihara M, Noda K, et al. Increased risk of lung cancer in Japanese smokers with class mu glutathione S-transferase gene deficiency. Cancer Lett (1993) 71:151–5.[CrossRef][Web of Science][Medline]
  143. 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) 16:2331–6.[Abstract/Free Full Text]
  144. 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.):S74–9.
  145. 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.[CrossRef][Web of Science][Medline]
  146. Kiyohara C, Wakai K, Mikami H, 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) 107:139–44.[CrossRef][Web of Science][Medline]
  147. Bonner MR, Rothman N, Mumford JL, et al. Green tea consumption, genetic susceptibility, PAH-rich smoky coal, and the risk of lung cancer. Mutat Res (2005) 582:53–60.[Web of Science][Medline]
  148. Lan Q, He XZ. Molecular epidemiological studies on the relationship between indoor coal burning and lung cancer in Xuan Wei, China. Toxicology (2004) 198:301–5.[CrossRef][Web of Science][Medline]
  149. Lewis SJ, Cherry NM, Niven RM, et al. GSTM1, GSTT1 and GSTP1 polymorphisms and lung cancer risk. Cancer Lett (2002) 180:165–71.[CrossRef][Web of Science][Medline]
  150. Li WY, Lai BT, Zhan XP. The relationship between genetic polymorphism of metabolizing enzymes and the genetic susceptibility to lung cancer. (In Chinese). Zhonghua Liu Xing Bing Xue Za Zhi (2004) 25:1042–5.[Medline]
  151. Li D, Zhou Q, Yuan T, et al. Study on the association between genetic polymorphism of CYP2E1, GSTM1 and susceptibility of lung cancer. Chin J Lung Cancer (2005) 8:14–19.
  152. Liang GY, Pu YP, Yin LH. Studies of the genes related to lung cancer susceptibility in Nanjing Han population, China. (In Chinese). Yi Chuan (2004) 26:584–8.[Medline]
  153. Cheng YW, Chen CY, Lin P, et al. DNA adduct level in lung tissue may act as a risk biomarker of lung cancer. Eur J Cancer (2000) 36:1381–8.[CrossRef][Web of Science][Medline]
  154. Lin P, Wang SL, Wang HJ, et al. Association of CYP1A1 and microsomal epoxide hydrolase polymorphisms with lung squamous cell carcinoma. Br J Cancer (2000) 82:852–7.[CrossRef][Web of Science][Medline]
  155. Wang YC, Chen CY, Wang HJ, 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) 62:402–10.[Medline]
  156. London SJ, Daly AK, Leathart JBS, et al. Lung cancer risk in relation to the CYP2C9*1/CYP2C9*2 genetic polymorphism among African-Americans and Caucasians in Los Angeles County, California. Pharmacogenetics (1996) 6:527–33.[CrossRef][Web of Science][Medline]
  157. London SJ, Yuan JM, Coetzee GA, et al. CYP1A1 I462V genetic polymorphism and lung cancer risk in a cohort of men in Shanghai, China. Cancer Epidemiol Biomarkers Prev (2000) 9:987–91.[Abstract/Free Full Text]
  158. Lu W, Xing D, Qi J, et al. Genetic polymorphism in myeloperoxidase but not GSTMI is associated with risk of lung squamous cell carcinoma in a Chinese population. Int J Cancer (2002) 102:275–9.[CrossRef][Web of Science][Medline]
  159. Song N, Tan W, Xing D, et al. CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: a case-control study in China. Carcinogenesis (2001) 22:11–16.[Abstract/Free Full Text]
  160. Luo C, Chen Q, Cao W, et al. Combined analysis of polymorphisms of GSTM1 and mutations of p53 gene in the patients with lung cancer. J Clin Oncol (2004) 31:1218–24.
  161. Matsuzoe D, Hideshima T, Iwasaki A, et al. Glutathione S-transferase µ1 null genotype is associated with K-ras gene mutation in lung adenocarcinoma among smokers. Carcinogenesis (2001) 22:1327–30.[Abstract/Free Full Text]
  162. Moreira A, Martins G, Monteiro MJ, et al. Glutathione S-transferase mu polymorphism and susceptibility to lung cancer in the Portuguese population. Teratog Carcinog Mutagen (1996) 16:269–74.[CrossRef][Web of Science][Medline]
  163. Nazar-Stewart V, Motulsky AG, Eaton DL, et al. The glutathione S-transferase µ polymorphism as a marker for susceptibility to lung carcinoma. Cancer Res (1993) 53:2313–18.[Abstract/Free Full Text]
  164. Nazar-Stewart V, Vaughan TL, Stapleton P, et al. A population-based study of glutathione S-transferase M1, T1 and P1 genotypes and risk for lung cancer. Lung Cancer (2003) 40:247–58.[CrossRef][Web of Science][Medline]
  165. Ng DPK, Tan KW, Zhao B, et al. CYP1A1 polymorphisms and risk of lung cancer in non-smoking Chinese women: influence of environmental tobacco smoke exposure and GSTM1/T1 genetic variation. Cancer Causes Control (2005) 16:399–405.[CrossRef][Web of Science][Medline]
  166. Zhao B, Seow A, Lee EJD, et al. Dietary isothiocyanates, glutathione S-transferase-M1,-T1 polymorphisms and lung cancer risk among Chinese women in Singapore. Cancer Epidemiol Biomarkers Prev (2001) 10:1063–7.[Abstract/Free Full Text]
  167. Hou SM, Fält S, Yang K, 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) 10:133–40.[Abstract/Free Full Text]
  168. Nyberg F, Hou SM, Hemminki K, et al. Glutathione S-transferase mu 1 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) 7:875–83.[Abstract]
  169. Oyama T, Kawamoto T, Mizoue T, et al. p53 mutations of lung cancer are not significantly affected by CYP1A1 or GSTM1 polymorphisms. Int J Oncol (1997) 11:305–9.[Web of Science]
  170. Ozturk O, Isbir T, Yaylim I, et al. GST M1 and CYP1A1 gene polymorphism and daily fruit consumption in Turkish patients with non-small cell lung carcinomas. In Vivo (2003) 17:625–32.[Web of Science][Medline]
  171. Perera FP, Mooney LA, Stampfer M, 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) 23:1641–6.[Abstract/Free Full Text]
  172. Perera FP, Mooney LA, Tang D, et al. Aromatic-DNA adducts, glutathione-S-transferase M1 and P1, and lung cancer risk in a nested case-control study. In: Proceedings of the annual meeting of the American Association for Cancer Research, vol 42. (2001) Philadelphia, PA: American Association for Cancer Research. 663.
  173. Pinarbasi H, Silig Y, Cetinkaya O, et al. Strong association between the GSTM1-null genotype and lung cancer in a Turkish population. Cancer Genet Cytogenet (2003) 146:125–9.[CrossRef][Web of Science][Medline]
  174. Qiao G, Wu Y, Zhen W, et al. A case-control study of GSTM1 deficiency and non-small-cell lung cancer. Acad J SUMS (2002) 23:25–7.
  175. Qu T, Shi Y, Peter S. The genotypes of cytochrome P450 1A1 and GSTM1 in non-smoking female lung cancer. Tumor (Shanghai) (1998) 18:80–2.
  176. Quiñones L, Lucas D, Godoy J, 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.[CrossRef][Web of Science][Medline]
  177. Reszka E, Tarkowski M, Szeszenia-Dabrowska N, et al. Glutathione S-transferase class mu (GSTM1) and pi (GSTP1) genetic polymorphism among lung cancer patients. (Abstract). Toxicology (2001) 164:153.
  178. Reszka E, Wasowicz W, Gromadzinska J, et al. Evaluation of selenium, zinc and copper levels related to GST genetic polymorphism in lung cancer patients. Trace Elem Electrolytes (2005) 22:23–32.
  179. Risch A, Wikman H, Thiel S, et al. Glutathione-S-transferase M1, M3, T1 and P1 polymorphisms and susceptibility to non-small-cell lung cancer subtypes and hamartomas. Pharmacogenetics (2001) 11:757–64.[CrossRef][Web of Science][Medline]
  180. Ruano-Ravina A, Figueiras A, Loidi L, et al. GSTM1 and GSTT1 polymorphisms, tobacco and risk of lung cancer: a case-control study from Galicia, Spain. Anticancer Res (2003) 23:4333–7.[Web of Science][Medline]
  181. Salagovic J, Kalina I, Stubna J, et al. Genetic polymorphism of glutathione S-transferases M1 and T1 as a risk factor in lung and bladder cancers. Neoplasma (1998) 45:312–17.[Web of Science][Medline]
  182. Schneider J, Bernges U, Philipp M, et al. GSTM1, GSTT1, and GSTP1 polymorphism and lung cancer risk in relation to tobacco smoking. Cancer Lett (2004) 208:65–74.[CrossRef][Web of Science][Medline]
  183. Seidegård J, Pero RW, Markowitz MM, et al. Isoenzyme(s) of glutathione transferase (class mu) as a marker for the susceptibility to lung cancer: a follow up study. Carcinogenesis (1990) 11:33–6.[Abstract/Free Full Text]
  184. Sgambato A, Campisi B, Zupa A, et al. Glutathione S-transferase (GST) polymorphisms as risk factors for cancer in a highly homogeneous population from southern Italy. Anticancer Res (2002) 22:3647–52.[Web of Science][Medline]
  185. 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.
  186. Sobti RC, Sharma S, Joshi A, et al. 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.[CrossRef][Web of Science][Medline]
  187. Sorensen M, Autrup H, Tjonneland A, et al. Glutathione S-transferase T1 null-genotype is associated with an increased risk of lung cancer. Int J Cancer (2004) 110:219–24.[CrossRef][Web of Science][Medline]
  188. Cauchi S, Stucker I, Solas C, et al. Polymorphisms of human aryl hydrocarbon receptor (AhR) gene in a French population: relationship with CYP1A1 inducibility and lung cancer. Carcinogenesis (2001) 22:1819–24.[Abstract/Free Full Text]
  189. Stucker I, Jacquet M, de Waziers I, et al. Relation between inducibility of CYP1A1, GSTM1 and lung cancer in a French population. Pharmacogenetics (2000) 10:617–27.[CrossRef][Web of Science][Medline]
  190. Stucker I, Hirvonen A, de Waziers I, et al. Genetic polymorphisms of glutathione S-transferases as modulators of lung cancer susceptibility. Carcinogenesis (2002) 23:1475–81.[Abstract/Free Full Text]
  191. Sun GF, Shimojo N, Pi JB, et al. Gene deficiency of glutathione S-transferase mu isoform associated with susceptibility to lung cancer in a Chinese population. Cancer Lett (1997) 113:169–72.[CrossRef][Web of Science][Medline]
  192. Sunaga N, Kohno T, Yanagitani N, et al. Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. Cancer Epidemiol Biomarkers Prev (2002) 11:730–8.[Abstract/Free Full Text]
  193. Taioli E, Crofts F, Trachman J, et al. A specific African-American CYP1A1 polymorphism is associated with adenocarcinoma of the lung. Cancer Res (1995) 55:472–3.[Abstract/Free Full Text]
  194. Taioli E, Ford J, Trachman J, et al. Lung cancer risk and CYP1A1 genotype in African Americans. Carcinogenesis (1998) 19:813–17.[Abstract/Free Full Text]
  195. Tang DL, Chiamprasert S, Santella RM, et al. Molecular epidemiology of lung cancer: carcinogen-DNA adducts, GSTM1 and risk. In: Proceedings of the annual meeting of the American Association for Cancer Research, vol 36. (1995) Philadelphia, PA: American Association for Cancer Research. 284.
  196. Tang DL, Rundle A, Warburton D, 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) 19:1949–53.[Abstract/Free Full Text]
  197. To-Figueras J, Gené M, Gómez-Catalán J, et al. Glutathione-S-transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev (1996) 5:337–42.[Abstract/Free Full Text]
  198. To-Figueras J, Gené M, Gómez-Catalán J, et al. Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms and lung cancer risk among Northwestern Mediterraneans. Carcinogenesis (1997) 18:1529–33.[Abstract/Free Full Text]
  199. To-Figueras J, Gené M, Gómez-Catalán J, et al. Genetic polymorphism of glutathione S-transferase P1 gene and lung cancer risk. Cancer Causes Control (1999) 10:65–70.[CrossRef][Web of Science][Medline]
  200. To-Figueras J, Gené M, Gómez-Catalán J, et al. Polymorphism of glutathione S-transferase M3: interaction with glutathione S-transferase M1 and lung cancer susceptibility. Biomarkers (2000) 5:73–80.[CrossRef][Web of Science]
  201. To-Figueras J, Gené M, Gómez-Catalán J, et al. Lung cancer susceptibility in relation to combined polymorphisms of microsomal epoxide hydrolase and glutathione S-transferase P1. Cancer Lett (2001) 173:155–62.[CrossRef][Web of Science][Medline]
  202. Tsai YY, McGlynn KA, Hu Y, et al. Genetic susceptibility and dietary patterns in lung cancer. Lung Cancer (2003) 41:269–81.[CrossRef][Web of Science][Medline]
  203. Wang JW, Deng YF, Cheng JL, et al. GST genetic polymorphisms and lung adenocarcinoma susceptibility in a Chinese population. Cancer Lett (2003) 201:185–93.[CrossRef][Web of Science][Medline]
  204. Wang JW, Deng YF, Li L, 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) 94:448–52.[CrossRef][Medline]
  205. Wang BG, Chen SD, Zhou WP, et al. A case control study on the impact of CYP450 MSPI and GST-M1 polymorphisms on the risk of lung cancer. (In Chinese). Zhonghua Zhong Liu Za Zhi (2004) 26:93–7.[Medline]
  206. Cote ML, Kardia SLR, Wenzlaff AS, et al. Combinations of glutathione S-transferase genotypes and risk of early-onset lung cancer in Caucasians and African Americans: a population-based study. Carcinogenesis (2005) 26:811–19.[Abstract/Free Full Text]
  207. Cote ML, Kardia SLR, Wenzlaff AS, et al. Combinations of glutathione S-transferase genotypes and risk of early-onset lung cancer in Caucasians and African Americans: a population-based study. (Erratum). Carcinogenesis (2005) 26:1158.[Free Full Text]
  208. Wenzlaff AS, Cote ML, Bock CH, et al. 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.[Abstract/Free Full Text]
  209. Wenzlaff AS, Cote ML, Bock CH, et al. GSTM1, GSTT1 and GSTP1 polymorphisms, environmental tobacco smoke exposure and risk of lung cancer among never smokers: a population-based study. (Erratum). Carcinogenesis (2005) 26:865.[Free Full Text]
  210. Wenzlaff AS, Cote ML, Bock CH, et al. CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study. Carcinogenesis (2005) 26:2207–12.[Abstract/Free Full Text]
  211. Woodson K, Ratnasinghe D, Bhat NK, et al. Prevalence of disease-related DNA polymorphisms among participants in a large cancer prevention trial. Eur J Cancer Prev (1999) 8:441–7.[Web of Science][Medline]
  212. 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) 13:686–8.
  213. Xian X, Chen S, Wang B. The relationship between polymorphism of GSTM1 and susceptibility to lung cancer. Pract Prev Med (2003) 10:635–7.
  214. Cheng TJ, Christiani DC, Wiencke JK, et al. Comparison of sister-chromatid exchange frequency in peripheral lymphocytes in lung-cancer cases and controls. Mutat Res Lett (1995) 348:75–82.[CrossRef]
  215. Cheng TJ, Christiani DC, Liber HL, et al. Mutant frequency at the hprt locus in human lymphocytes in a case-control study of lung cancer. Mutat Res (1995) 332:109–18.[Web of Science][Medline]
  216. Cheng TJ, Christiani DC, Xu XP, et al. Increased micronucleus frequency in lymphocytes from smokers with lung cancer. Mutat Res (1996) 349:43–50.[CrossRef][Web of Science][Medline]
  217. Liu G, Miller DP, Zhou W, et al. Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma. Cancer Res (2001) 61:8718–22.[Abstract/Free Full Text]
  218. Miller DP, Liu G, De Vivo I, et al. Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. Cancer Res (2002) 62:2819–23.[Abstract/Free Full Text]
  219. Wang LI, Christiani DC. Cruciferous vegetable intake, glutathione S-transferase mu-1 (GSTM1) polymorphism and lung cancer risk. (Abstract). Am J Epidemiol (2002) 155(suppl):S51.
  220. Wang LI, Giovannucci EL, Hunter D, et al. Dietary intake of cruciferous vegetables, glutathione S-transferase (GST) polymorphisms and lung cancer risk in a Caucasian population. Cancer Causes Control (2004) 15:977–85.[CrossRef][Web of Science][Medline]
  221. Xu X, Kelsey KT, Wiencke JK, et al. Cytochrome P450 CYP1A1 MspI polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev (1996) 5:687–92.[Abstract/Free Full Text]
  222. Xue K, Xu L, Cheng S, et al. Polymorphism of CYP1A1, GSTM1 and lung cancer susceptibility in the Chinese population. (In Chinese). (Abstract). Teratog Carcinog Mutagen (1999) 11:326.
  223. Yang XH, Wacholder S, Xu ZY, et al. CYP1A1 and other single nucleotide polymorphisms in relation to lung cancer risk: a case-control study of women in north-east China. (Abstract). Cancer Epidemiol Biomarkers Prev (2002) 11(suppl):1223S.
  224. Yang XHR, Wacholder S, Xu ZY, et al. CYP1A1 and GSTM1 polymorphisms in relation to lung cancer risk in Chinese women. Cancer Lett (2004) 214:197–204.[CrossRef][Web of Science][Medline]
  225. Yang P, Bamlet WR, Ebbert JO, et al. Glutathione pathway genes and lung cancer risk in young and old populations. Carcinogenesis (2004) 25:1935–44.[Abstract/Free Full Text]
  226. Ye W, Chen Q, Chen S. Study on relationship between GSTM1 polymorphism, diet factors, and lung cancer. Chin J Public Health (2004) 20:1120–1.
  227. Zhang J, Hu Y, Yu C, et al. Polymorphism of GSTM1 and T1 and lung cancer susceptibility. Chin J Pathophysiol (2002) 18:352–5.
  228. Zhang J, Hu Y, Yu C, et al. Study on genetic polymorphisms of GSTM1 and GSTT1 related with inherent susceptibility to lung cancer in women. Chin J Public Health (2002) 18:273–5.

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