GSTM1, GSTT1 and GSTP1 polymorphisms, environmental tobacco smoke exposure and risk of lung cancer among never smokers: a population-based study
A.S. Wenzlaff1,*,
M.L. Cote1,
C.H. Bock1,
S.J. Land1,3 and
A.G. Schwartz1
1 Population Studies and Prevention Program, 2 Center for Molecular Medicine and Genetics and 3 Molecular Biology and Human Genetics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
* To whom correspondence should be addressed Email: wenzlaff{at}med.wayne.edu
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Abstract
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Glutathione S-transferases detoxify polycyclic aromatic hydrocarbons found in tobacco smoke by glutathione conjugation. Polymorphisms within the GSTM1, GSTT1 and GSTP1 genes, coding for enzymes with deficient or reduced activity, have been studied as potential modifiers of lung cancer risk. It is hypothesized that risk associated with potential susceptibility gene polymorphisms might be most evident at low levels of exposure. Never smokers developing lung cancer represent a highly susceptible subset of the population, exposed to tobacco carcinogens only through environmental tobacco smoke. This population-based case-control study examines the association between GSTM1, GSTT1 and GSTP1 genotypes and lung cancer in one of the largest samples of never smokers to date. Cases (n = 166) were identified through the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) program and age- and race-matched population-based controls (n = 181) were identified using random digit dialing. Overall, there was no significant association between single or combinations of genotypes at GSTM1, GSTT1 or GSTP1 and lung cancer risk after adjustment for age, race, sex and household ETS exposure in years. However, in never smokers exposed to 20 or more years of household ETS, carrying the GSTM1 null genotype was associated with a 2.3-fold increase in risk [95% confidence interval (CI) 1.055.13]. Individuals in this high ETS exposure category carrying the GSTM1 null and the GSTP1 Val allele were at over 4-fold increased risk of developing lung cancer (OR = 4.56, 95% CI: 1.2117.21). These findings suggest that in the presence of ETS, the GSTM1 genotype both alone and in combination with the GSTP1 genotype alters the risk of developing lung cancer among never smokers.
Abbreviations: CI, confidence interval; ETS, environmental tobacco smoke; ITC, isothiocyanates; OR, odds ratio
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Introduction
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In 2004, over 173 000 new lung cancer diagnoses and 160 000 lung cancer deaths are expected in the US (1). While it is well recognized that 8090% of all lung cancer is attributable to cigarette smoking, only 15% of all smokers develop this disease and
10% of all diagnoses are among never smokers (2). This suggests that there is great individual variation in susceptibility to lung carcinogens. Never smokers developing lung cancer represent an understudied population even though the estimated number of deaths from this disease in never smokers alone is approximately equal to the number of deaths from ovarian cancer annually (1). Most never smokers with lung cancer have been exposed to tobacco smoke through environmental tobacco smoke (ETS). Developing lung cancer despite this lower level of exposure suggests that never smokers represent a particularly susceptible subset of the general population.
It is hypothesized that a large proportion of lung cancer susceptibility is determined by the balance between an individual's capacity to activate and detoxify carcinogens in tobacco smoke. Glutathione S-transferases (GSTs), which comprise one superfamily of phase II detoxification enzymes, detoxify polycyclic aromatic hydrocarbons found in tobacco smoke by conjugating them with glutathione (3). Polymorphisms exist within the GSTM1, GSTT1 and GSTP1 genes, the focus of this analysis. Both the GSTM1 and the GSTT1 null variants result in the lack of enzyme production. GSTP1 is the most abundant isoform in the lung. One polymorphism in GSTP1, an Ile to Val conversion at codon 105, has been reported to result in an enzyme with reduced activity (4). It is possible that deficient or reduced activity of these enzymes might result in an increased susceptibility to cancer.
While a number of studies have evaluated lung cancer risk associated with GST polymorphisms in smokers, studies of never smokers have been limited in size and in number. Studies of GSTM1 have shown increased lung cancer risk associated with having the null variant both in non-smokers (5) and in heavy smokers (6). A recent meta-analysis estimates increased lung cancer risk associated with the GSTM1 null genotype is moderate [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.071.27) (7)]. Individual studies of GSTT1 and GSTP1 variants have been conducted predominantly in smoking populations and have yielded conflicting results (5,6,810). These two polymorphisms are most often associated with lung cancer risk only in conjunction with at least one additional GST variant allele (11,12).
The objective of this study is to jointly evaluate the association between GSTM1, GSTT1 and GSTP1 polymorphisms and lung cancer risk in never smokers with low levels of exposure using a population-based case-control approach. Another group suspected to be susceptible at low levels of exposure includes those diagnosed at an early age. One of the studies included in the analysis is focused specifically on individuals under the age of 50, so the analysis is enriched for those thought to have a heightened risk potentially mediated through genetic variation in metabolic activity.
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Materials and methods
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Study subjects
Lifetime never smokers were identified through two case-control studies. The first study included individuals newly diagnosed between 1984 and 1987, age 4084 years (Study 1) (13) and the second (ongoing) study includes lung cancer cases under age 50 years, newly diagnosed on or after September 15, 1990 (Study 2). Study 2 was conducted in three phases, with phase I limited to those under age 40, phase II included those under age 45 and the current phase III, which includes individuals under the age of 50. In both Study 1 and Study 2, cases were identified through the population-based Metropolitan Detroit Cancer Surveillance System (MDCSS), a participant in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Population-based controls were identified through random digit dialing. A greater proportion of controls than cases were lifetime never smokers, so controls were randomly selected from within each study to match never smoking cases on race, sex, 5-year age group and county of residence. Whenever possible, controls were frequency matched to cases in a 1:1 ratio in Study 1 and 2:1 in Study 2. Lifetime never smokers in both studies were defined as individuals smoking fewer than 100 cigarettes in their lifetimes.
The overall interview response rate was 66.1% for cases. It was not possible to calculate a response rate for controls because eligibility could not be determined in households refusing to answer the eligibility screening questionnaire. Of those individuals answering the telephone and providing a household census to determine eligibility, 93.0% participated in the study.
Data and biosample collection
All local institutional and review boards approved this study. Informed consent was obtained from each subject prior to study participation. Trained interviewers conducted telephone interviews to collect demographic information, smoking history, health history and lifetime estimates of ETS exposure. If the study subject was unable to participate due to illness or death, an attempt was made to obtain proxy data by interviewing someone familiar with the subject's history. Demographic information included date and place of birth, residence at time of diagnosis, marital status, race and number of years of education completed. Medical history included physician diagnoses of asthma, emphysema, allergies, pneumonia, bronchitis, chronic obstructive pulmonary disease, tuberculosis and cancer. Year of first diagnosis of each illness was also requested, when applicable. Participants were asked about their ETS exposure at home and the workplace, as well as hours and years of exposure in each location. Family history of lung cancer was coded as yes or no based on detailed first-degree family history information collected. Lung cancer diagnosis dates and histology information for cases were obtained through the MDCSS.
Biological samples were collected from cases and controls through blood, buccal swabs and tissue blocks. Samples were available for 166 never smoking cases and 181 selected never smoking controls. Case biospecimens consisted of 17 blood, five buccal and 144 tissue block samples. Normal tissue could be extracted from 54 of the blocks, 58 were determined to be mixed and 32 were mostly tumor. Among the controls, 95 blood and 86 buccal samples were available for analysis. A small number of these cases and controls could not be genotyped at varying polymorphisms due to poor sample quality.
Genotyping
DNA was isolated from whole blood with the Genomic DNA Purification System (Gentra Systems, Minneapolis, MN), buccal swabs with the BuccalAmpTM DNA Extraction Kit (Epicentre Technologies, Madison, WI), or paraffin-embedded tissue with the QIAamp DNA Mini Kit (Qiagen, Valencia, CA) following the manufacturers' protocols. When multiple tissues were obtained from a study participant, DNA extracted from blood was used preferentially, followed by DNA extracted from buccal swabs and then DNA extracted from normal tissue in paraffin blocks. To evaluate whether there might be allelic loss or somatic mutations in the GSTs in the tumor tissue we compared genotype results for normal versus mixed and tumor tissue blocks. No differences in genotype distribution were observed by tissue type (normal only versus mixed/tumor).
2 P-values comparing allele frequencies for GSTM1, GSTT1 and GSTP1 among normal versus mixed and tumor tissue were 0.52, 0.39 and 0.27, respectively.
DNA isolated from buccal cells or paraffin-embedded tissue was pre-amplified using a nested PCR strategy. Outer amplification was carried out in a 25 µl reaction containing 2.5 mmol/l MgCl2, 0.5 µmol/l of the gene-specific primers, 1.25 U AmpliTaq Gold polymerase, and 200 µmol/l of dATP, dCTP, dGTP and dTTP. The outer amplification mixture was denatured at 95°C for 10 min and amplification was achieved by 15 cycles of 94°C for 30 s, 63°C for 30 s and 72°C for 1 min, followed by a final extension at 72°C for 10 min. The outer amplification was performed on a Mastercycler® Gradient thermocycler (Eppendorf, Westbury, NY). Gene-specific allelic discrimination (as described below) was determined directly from amplification of DNA from whole blood or pre-amplified DNA from buccal or paraffin-embedded tissue. Five percent of the products were randomly sequenced and 10% of genotypes were carried out in duplicate. Table I lists the sequences of the primers and probes used in genotyping GSTM1, GSTT1 and GSTP1 polymorphisms. Beta-globin was used as an amplification control for the null mutations of GSTM1 and GSTT1. No template controls and sequenced controls were used for all assays.
The GSTM1 null mutation was assayed using quantitative PCR methods as described previously (14). Briefly, 25 ng of DNA extracted from whole blood or 2 µl of pre-amplification reaction was mixed with forward (GSTM1-194F) and reverse (GSTM1-273-2) primer and the product was detected with a fluorescent probe (GSTM1-215T) at an annealing temperature of 55°C.
The GSTT1 null mutation was determined as described previously (15). Briefly, following amplification with an annealing temperature of 58°C, the PCR products were electrophoresed through 3% NuSieve 3:1 agarose (FMC) and visualized with ethidium bromide.
Primers for amplification of the region of the GSTP1 gene containing the functional polymorphism and fluorescent probes for allelic discrimination were designed using Primer Express software (Applied Biosystems). Standard TaqMan conditions were applied in an ABI PRISM 7900 Sequence Detection System (Applied Biosystems) for amplification and detection of both alleles. Briefly, 25 ng of DNA derived from whole blood or 2 µl of pre-amplification reaction was added to 1x Universal PCR mix (Applied Biosystems) containing forward (GSTP1-IF) and reverse (GSTP1-IR) primers and GSTP1 A313 allele (GSTP1-A) and GSTP1 G313 allele (GSTP1-G) probes at an annealing temperature of 64°C.
Statistical analysis
Allele frequencies for each polymorphism were calculated for cases and controls, stratifying by race. For GSTM1 and GSTT1, our genotyping methods did not distinguish between homozygous non-null and heterozygous individuals. Therefore, HardyWeinberg equilibrium tests of genotype distribution in controls, by race, were conducted only for GSTP1. The effect of each GST variant and each combination of GST variants on lung cancer risk was tested in unconditional logistic regression models, adjusting for age at diagnosis (cases)/interview (controls), race (Caucasian/African American), sex and years exposed to household ETS. To increase the study power when testing genegene interactions, GSTP1 genotypes were collapsed so that individuals with at least one valine allele (Ile/Val or Val/Val) were compared with individuals carrying the Ile/Ile genotype. Inclusion of ETS at work, education, history of congestive lung diseases and family history of lung cancer did not alter results in the multivariate models and therefore were not included in the final models. ORs and 95% CIs for each genotype were calculated from coefficients in the final models. Analyses were repeated after stratification by histology, ever/never exposure to household ETS, and years of household ETS exposure. The CochranArmitage test was used to assess possible linear trends in stratified data and power calculations were conducted (16). All statistical analyses were performed using SAS version 8.02.
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Results
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Demographics for cases and controls are shown in Table II. The mean age was 62.4 years for the cases and 54.9 years for the controls (P < 0.001). This age difference was due to the oversampling of non-smoking controls from Study 2, where the participants were younger. Among those reporting ETS exposure, the mean number of years of household ETS exposure was greater in cases (28.2 years) than controls (23.8 years) (P = 0.02). There were no significant differences in sex or race between cases and controls (P = 0.19 and P = 0.57, respectively). Cases were less likely to have finished high school than controls and had significantly lower education levels overall. In this group of lifetime never smokers, adenocarcinoma was the most prominent histological type (54.2%), with squamous cell carcinoma as the second most common histologic type (15.7%).
Genotype data were available for GSTM1 for 160 cases and 177 controls, for GSTT1 for 153 cases and 175 controls, and for GSTP1 for 141 cases and 180 controls. Allele frequencies for these polymorphisms are reported in Table III. The GSTP1 genotype distribution for the total sample of controls was in HardyWeinberg equilibrium (
2 P-value = 0.35), as were the distributions in controls by race (
2 P-value = 0.64 in Caucasians and
2 P-value = 0.17 in African Americans). Racial differences in allele frequencies in the controls were seen only for GSTM1, with African Americans having a lower frequency of the null allele (27%) than Caucasians (52%) (P = 0.01).
There was no significant association between genotype at GSTM1 and lung cancer risk after adjustment for age at diagnosis (cases)/interview (controls), sex, household ETS exposure in years and race where appropriate (Table IV). The allele frequency distribution for GSTM1 varied significantly by race. While there were no observed differences in risk for the GSTM1 null genotype among Caucasians, there was a non-significant 2-fold increase in risk in African Americans (OR = 1.92, 95% CI: 0.497.45).
Neither the GSTT1 null variant nor the GSTP1 Val allele was found to be significantly associated with lung cancer risk among never smokers, a finding that was similar across racial groups (Table IV). While none of the findings were statistically significant, ORs estimating the association between GSTT1 null variant and lung cancer risk were all <1. Evaluation of combinations of GST genotypes (Table IV) also revealed no significant association between genotypes and the development of lung cancer among never smokers.
In this group of never smokers, exposure to tobacco carcinogens was in the form of ETS. Risk of lung cancer increased with increasing quartile of household ETS exposure, however, the trend was not statistically significant (CochranArmitage two-sided P-value = 0.08) (data not shown). Stratifying by ever/never household ETS exposure demonstrated increased risks for GSTM1 null individuals with at least some ETS exposure. Furthermore, the interaction between GSTM1 null and quartile of household ETS exposure years was significant in the full analysis model (P = 0.01). To investigate this possible interaction and still maintain study power, individuals were stratified into no household ETS exposure, <20 household ETS years (the median level among exposed controls and
20 years of household ETS). Among individuals with no household ETS exposure, there appeared to be a protective effect for the GSTM1 and GSTT1 null genotypes individually, although these associations were not statistically significant (GSTM1 OR = 0.52, 95% CI: 0.221.23; GSTT1 OR = 0.32, 95% CI: 0.101.03). Carrying the null genotype in both of these genes was associated with reduced risk of lung cancer in those not exposed to ETS (OR = 0.16, 95% CI: 0.030.93), however, this group included only two cases and six controls. No single genotype or combination of genotypes was significantly associated with lung cancer among individuals with greater than zero and less than the median exposure (Table V). Among individuals with the median ETS exposure or greater, however, having the null variant of GSTM1 more than doubled the risk of lung cancer (OR = 2.32, 95% CI: 1.055.13). Similarly, carrying both the GSTM1 null variant and a valine residue at the GSTP1 locus was associated with a 4-fold increased risk of lung cancer among those with greater ETS exposure (OR = 4.56, 95% CI: 1.2117.21). Power calculations based on available sample size indicated 70% power to detect a true OR of 2.08 among individuals with one or two risk genotypes for the GSTM1/GSTP1 combination or a 60% power to detect a true OR of 1.67. Stratification by histologic type did not reveal any significant differences in the results (data not shown).
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Discussion
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Numerous previous studies of GSTM1 genotype in smokers have reported moderate increases in lung cancer risk associated with the null genotype [meta-analysis (7)]. Less has been reported for GSTT1 and GSTP1 polymorphisms, particularly in never smokers, and for combinations of all these polymorphisms. In our study, the GSTM1 null genotype and the GSTM1 null/GSTP1 Val combination were associated with increased lung cancer risk in never smoking individuals with 20 or more years of household ETS exposure. Studies focusing solely on the risk of lung cancer in never smokers have been limited in size and in number. A recent report by Hung et al. used pooled data collected on non-smoking lung cancer cases and controls from 14 primarily European studies and reported no significant association between the GSTM1 null genotype and lung cancer (17). Through stratification of cases by ETS levels, Bennett et al. showed a strong interaction between the GSTM1 null genotype and higher ETS exposure, including a significant trend. Kiyohara et al. reported no significant increase in lung cancer risk associated with the GSTM1 null genotype in non-smoking individuals with low ETS exposure, but an over 2-fold increase among individuals with 40 or more packyears of ETS exposure in a hospital-based case-control study conducted in Japan (18). Similar suggestive, but not statistically significant, findings for increased risk associated with ever exposure to ETS among non-smokers carrying the GSTM1 null genotype were reported in a primarily European case-control study (19). Our population-based study is one of the largest of never smokers and our findings support an association between the GSTM1 null genotype and increased lung cancer risk among individuals with high ETS exposures. This is consistent with the hypothesis that reduced ability to detoxify tobacco carcinogens in ETS through the enzymatic activity of GSTM1 contributes to lung cancer susceptibility.
Increased risk is even more evident in never smokers with 20 or more years of household ETS exposure who carry both the GSTM1 null and at least one Val allele at GSTP1. Similar findings of increased lung cancer risk associated with carrying the GSTM1 null/GSTP1 Val allele genotype were reported by Wang et al., however this study included only 64 non-smoking cases (20). Miller et al. report increased (although not statistically significant) risk of lung cancer associated with ETS exposure (OR = 1.62, 95% CI: 0.515.14) among non-smokers (n = 66 cases) carrying the GSTP1 Val/Val genotype, while those carrying the Ile/Ile genotype had lower risks associated with ETS exposure (21). While Miller's results are not statistically significant, they support the findings reported here. Studies of GSTP1 in smokers, either alone or in combination with other genotypes, have reported conflicting results. In only two of nine studies of GSTP1 alone (reviewed in ref. 22), the exon 5 GSTP1 Val low activity allele was associated with an
2-fold increased risk of developing lung cancer. In a recent hospital-based study, Wang et al. reported no association between the exon 5 polymorphism and lung cancer risk, but did find evidence of risk associated with the exon 6 Ala114Val polymorphism (OR = 1.40, 95% CI: 1.031.91) (10). Nazar-Stewart et al. evaluated GSTP1 in combination with GSTM1 and found no increased risk associated with the exon 5 polymorphism (6). Two other studies of this combined genotype support our findings (23,24). The apparently conflicting findings in the literature suggest complex interactions between genetic polymorphisms, metabolism of tobacco carcinogens and smoking patterns. More than one GST isoform is responsible for the detoxification of tobacco smoke carcinogens. GSTP1 codes for the most abundant isoform in the lung and it would be expected that further reduction in detoxification ability from carrying risk genotypes at two loci would increase risk under certain exposure conditions. The increase in risk associated with decreased detoxification activity may only be evident when exposures are relatively low, as we see in never smokers exposed to ETS, and when multiple enzymes in a pathway are lacking.
Findings of associations between GSTT1 and lung cancer have been less consistent than findings for GSTM1, some suggesting a possible interaction with smoking. Among studies of mostly smokers, the GSTT1 null genotype has been associated with increased lung cancer risk (25,26) and no difference in risk (6). Although not statistically significant, our study found that never smokers who reported no household ETS exposure and who were GSTT1 null were at one-third the risk of lung cancer than individuals not GSTT1 null. A possible protective effect of being GSTT1 null in non-smokers has also been reported by Hou et al. (27). The potential protective effect of the GSTT1 null genotype in never smokers without ETS exposure suggests that there are non-tobacco related exposures that need to be explored. One possibility is that never smokers deficient in GSTT1 (GSTT1 null) who consume foods rich in isothiocyanates (ITC) are protected against lung cancer. ITCs are found in cruciferous vegetables, are substrates for GSTs, and are associated with reduced cancer risk. Reduced intake of ITCs has been associated with increased risk of lung cancer in current smokers who are either GSTM1 or GSTT1 null (26). London et al. demonstrated in a cohort of Chinese men that individuals with detectable levels of ITC who were either GSTM1 or GSTT1 null were at reduced risk of lung cancer (28). We did not measure ITC intake so we cannot look at this directly in our study.
While differences in histology types and possible carcinogenesis pathways between non-smokers and smokers are hypothesized, differences in risk related to varying levels of ETS in non-smokers have not been well categorized. Stratifying this population of never smokers by histology did not reveal significant differences in risk by ETS levels or GST genotype.
Despite the large sample of Caucasian and African American population-based never smokers included in this study, analyses by race and ETS exposure were limited by the small number of cases. In particular, our power to detect a true difference in lung cancer risk for GST combinations was limited. Our finding of a 4-fold increase in lung cancer risk associated with the combination of GSTM1 and GSTP1 risk genotypes must therefore be considered with caution. In addition, estimates of ETS exposure are subject to misclassification. Both estimates of lifetime years and hours of ETS exposure were collected, however, years of exposure was chosen for the analysis because we believe that it was a more reliable measure than the estimates of hours exposed. Another potential limitation of this study is the difference in mean ages of the cases and controls. Younger controls were more likely to provide a blood sample than older controls and were over-sampled. However, none of the genotype distributions varied by age (comparing those <55 years, the mean age in the controls, to those age 55 and older) in either cases or controls, so it is unlikely that this age difference confounded the results (data not shown). Additionally, age was included in all the multivariate models. While not all subjects interviewed provided biologic specimens for genotyping, the observed allele frequencies for each genotype in our controls are comparable with those reported in the literature (6,17).
It is only recently that studies have evaluated combinations of polymorphisms for a possible association with lung cancer risk and few studies have evaluated these combinations among never smokers. Our study of lifetime never smokers has identified significant differences in lung cancer risk associated with both GSTM1 null and GSTM1 null/GSTP1 Val combined genotypes in the presence of high levels of ETS exposure. Because these polymorphisms play important overlapping roles in detoxifying tobacco carcinogens and because risk associated with these polymorphisms might only be evident at low exposure levels (such as ETS exposure rather than active smoke exposure) (29), the continued study of risk associated with multiple polymorphisms simultaneously among low exposure groups is essential. While studies of high frequency, low penetrant candidate susceptibility genes, including the GSTs, have not been as revealing as originally hoped (30,31), continued study in large populations is needed to fully understand the complexities underlying susceptibility. This is likely to be best accomplished through collaborative consortiums.
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Acknowledgments
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The authors thank Donald R.Schwartz, PhD, for his technical assistance. This work was supported by NCI Grant R01-CA60691, Contract N01-CN65064 and Contract N01-PC-35145.
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Received June 28, 2004;
revised September 30, 2004;
accepted October 26, 2004.