Glutathione S-transferase M1 polymorphism and lung cancer risk in African-Americans

Jean G. Ford1,2,8, Yongliang Li1,2, Mary Margaret O'Sullivan3, Rita Demopoulos4, Seymour Garte5, Emanuela Taioli6,7 and Paul W. Brandt-Rauf2

1 Division of Pulmonary and Critical Care Medicine, Harlem Hospital Center, Columbia College of Physicians and Surgeons, New York, NY 10037,
2 Division of Environmental Health Science, Joseph L.Mailman School of Public Health at Columbia University, New York, NY 10032,
3 St Luke's–Roosevelt Hospital Center, Columbia University, New York, NY 10025,
4 Kaplan Comprehensive Cancer Center New York University, New York, NY 10016,
5 EOHSI, UMDNJ, Piscataway NJ 08854,
6 Department of Environmental Medicine, New York University, New York, NY 10016, USA and
7 Ospedale Policlinico IRCCS, Milano 20122, Italy


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Glutathione S-transferase M1 (GSTM1) can detoxify many carcinogens, including polycyclic aromatic hydrocarbons such as those from cigarette smoke. Though a number of studies have been published about the association between GSTM1 polymorphism and lung cancer, this association has received limited attention in the African-American population. We conducted a case–control study to investigate the role of GSTM1 polymorphism in the development of lung cancer in African-Americans. Specimens of DNA from 117 lung cancer cases and 120 controls were assayed for detection of GSTM1 genotype by polymerase chain reaction (PCR). The odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with homozygous deletion of the GSTM1 gene and other risk factors were estimated by logistic regression. Thirty-seven of the 117 cases (31.6%) and 24 of the 120 controls (20.0%) had the GSTM1 null genotype; the OR was 2.10 (95% CI 1.07–4.11) after adjustment for age, gender and smoking. The association was higher for squamous cell carcinoma (OR 2.98, 95% CI 1.09–8.19) than for adenocarcinoma (OR 1.95, 95% CI 0.81–4.66). We observed a stronger association between GSTM1 null genotype and lung cancer among heavy smokers with >=30 pack-years (OR 4.35, 95% CI 1.16–16.23). This association was also found in squamous cell carcinoma (OR 6.26, 95% CI 1.31–29.91). In the analysis combining GSTM1 polymorphism and smoking, smokers with the null genotype had high risk (OR 8.19, 95% CI 2.35–28.62) compared with non-smokers with the wild-type genotype, and the risk increased with smoking cigarette pack-years (P = 0.0001 for trend). Our results suggest that GSTM1 polymorphism plays a role in the development of lung cancer and modifies the risk for smoking-related lung cancer in African-Americans.

Abbreviations: CI, confidence interval; GSTM1, glutathione S-transferase M1; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon; PCR, polymerase chain reaction.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Cigarette smoking is known to be the most common risk factor for lung cancer, and the risk increases with exposure to cigarette smoke over a lifetime (1). Cigarette smoke contains several thousand chemicals, of which about 50 compounds are known carcinogens, including polycyclic aromatic hydrocarbons (PAHs). Some of these compounds are reactive carcinogens, but most are pro-carcinogens, which need to be activated by phase I enzymes such as those encoded by the cytochrome 450 (CYP 450) supergene family, and converted into reactive carcinogens. All these reactive carcinogens can bind to DNA and form DNA adducts capable of inducing mutations and initiating carcinogenesis.

Phase II enzymes can detoxify many carcinogens, such as those from cigarette smoke and its metabolites, and protect DNA against damage including adduct formation. The glutathione S-transferase (GST) is a supergene family that can be divided into four different classes: {alpha}, µ, {pi} and {theta}, in humans (2). Each class contains several genes, except the {pi} class, which has only one. GSTs act as phase II enzymes, through glutathione conjugation to electrophilic substances. Glutathione S-transferase M1 (GSTM1), a GST µ class isoenzyme, plays an important role in the detoxification of carcinogens, such as PAHs. It is polymorphic and has been extensively studied in relation to cancer. About 50% of the Caucasian population and 20–30% of African-Americans lack this GSTM1 gene (null genotype). In general, individuals who lack the GSTM1 gene have increased susceptibility to carcinogens and are more likely to develop cancer than those who have this gene. Results of many molecular epidemiological studies concerning the association between GSTM1 polymorphism and lung cancer have been contradictory. Several studies of both phenotype and genotype have indicated that the GSTM1 null genotype is associated with lung cancer, and the risk of lung cancer increased with the lifetime smoking history (37). Other investigators, however, have not found this association (812). Recent reviews of the literature in this area have found a mild association between lung cancer and GSTM1 polymorphism (13,14).

Though a number of studies have been published on the association between lung cancer and GSTM1 polymorphisms, most have been conducted in Caucasian and Japanese populations (312), and there are few data (15,16) on this association in African-Americans. We conducted a case–control study to examine the role of GSTM1 polymorphisms in the development of lung cancer and modification of lung cancer risk factors, such as smoking, in African-Americans.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
We recruited 52 patients with primary lung cancer among African-Americans at three affiliated hospitals of Columbia University (Harlem Hospital Center, Columbia-Presbyterian Medical Center and St Luke's–Roosevelt Hospital Center) from 1992 to 1996 and another 65 patients with primary lung cancer among African-Americans at New York University Medical Center from 1984 to 1992. All cases were newly diagnosed and histologically proven. The patients enrolled had undergone either surgical intervention or lung biopsy, the latter showing the presence of small cell carcinoma. Among the African-American patients recruited from the Columbia affiliated hospitals, most (47 out of 52 subjects) were from Harlem Hospital Center. The African-American lung cancer subjects admitted at Columbia–Presbyterian Medical Center and St Luke's–Roosevelt Hospital were randomly included, and a random sample of the lung cancer subjects admitted at Harlem Hospital Center (47 subjects from a total of 145 subjects) were recruited. Patients from New York University were all of the available primary lung cancers drawn from the cancer registry. Tissue blocks were obtained for DNA extraction; four patients were excluded because tissue was not available. One hundred and twenty controls were a random sample of patients with a variety of diseases other than cancer, such as asthma, hypertension, heart disease and tuberculosis, who came to the Pulmonary Division or Department of Medicine of Columbia affiliated hospitals for medical evaluation from 1994 to 1996. All subjects provided their signed, informed consent before enrolment into the study. The subjects from Columbia affiliated hospitals responded to a structured questionnaire that was administered by the same trained interviewers. The questionnaire contained information on demographic characteristics and smoking history, including current smoking status, the average number of packs of cigarettes smoked per day and the number of years of smoking. The number of pack-years of smoking (packs per dayxsmoking years) was calculated from this information and the subjects were categorized as current smokers (had smoked within last 6 months), ex-smokers (had stopped smoking >=6 months before the diagnosis) and non-smokers (had never smoked). For 12 lung cancer patients from Harlem Hospital Center who could not be interviewed, the information on demographic characteristics and smoking was collected from the Harlem Hospital Tumor Registry. In order to examine the reliability of the Tumor Registry data, 20 patients for whom data were available from both interview and the Tumor Registry were randomly selected. The information on demographic characteristics and smoking were essentially the same among the 20 cancer patients, suggesting that both sources were equally reliable. For patients recruited at New York Medical Center, medical charts were reviewed to obtain demographic information and smoking history.

Assay for GSTM1
A 30 ml blood sample was collected from each participant at the Columbia University affiliated hospitals in a heparinized tube, transferred to the laboratory and coded. Plasma, buffy coat and red blood cells were separated by centrifugation, aliquoted and stored at –70°C until assay. DNA was extracted from buffy coats by the routine phenol–chloroform method. For 10 cancer patients and two controls whose blood samples were drawn without heparin and whose buffy coats were not obtained, DNA was extracted from serum using a QIAamp blood kit (Qiagen) according to the manufacturer's instructions. Archived tissue blocks of the subjects from New York University Medical Center were obtained and DNA extracted by routine method as described previously (17).

GSTM1 polymorphisms were assayed using a modified polymerase chain reaction (PCR) method, as described by Bell et al. (18). Briefly, 100 ng of DNA was added to the PCR reaction mixture containing reaction buffer (10 mM Tris–HCl, 50 mM KCl and 1.5 mM MgCl2), 0.2 mM dNTPs, 0.8 units Taq polymerase, 60 ng GSTM1 primer pair 5'-GAACTCCCTGAAAAGCTAAAGC and 5'-GTTGGGCTCAAATATACGGTGG and 30 ng ß-globin primer pair 5'-CAACTTCATCCACGTTCACC and 5'-GAAGAGCCAAGGACAGGTAC. The amplification of ß-globin was used as an internal control in this procedure. The reaction mixture was denatured at 94°C for 4 min and then subjected to 34 cycles of 94°C for 20 s, 55°C for 30 s and 72°C for 1 min followed by a final 72°C extension for 5 min. The PCR product was examined by electrophoresis in an 8% polyacrylamide gel followed by staining with ethidium bromide. A 273 bp band (ß-globin gene) and a 219 bp band (GSTM1 gene) were identified and photographed under UV light. The subject was identified as homozygous deletion (null genotype) of GSTM1 gene when there was a 273 bp ß-globin band but no 219 bp GSTM1 band in the sample. Mixed samples of cases and controls were analysed together by an examiner who did not know the sample status.

Statistical methods
The difference in age between cases and controls was examined by Student's t-test. The Mantel–Haenszel method was used for univariate analysis of gender and smoking status. Unconditional logistic regression was used for the association between GSTM1 polymorphisms and lung cancer to estimate odds ratios (ORs) and their 95% confidence interval (95% CI). Age was modeled as a continuous variable. Age and gender were entered into all models. All analyses were performed in PC SAS version 6.12 for Windows (SAS Institute, Cary, NC, USA). All P values presented in this study were two-sided.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 117 lung cancer patients and 120 controls, all African-Americans, voluntarily participated in this study. Some characteristics of this study population are presented in Table IGo. Compared with the controls, the cases were significantly older (P = 0.003) and more likely to be male (P < 0.0001). As expected, there were more smokers among the cancer patients than among the controls. Only 6% of the cancer patients had never smoked cigarettes, compared with 20.2% of controls; the OR for lung cancer was 1.90 (95% CI 0.67–5.45, P = 0.2299) for ex-smokers and 4.79 (95% CI 2.06–11.14, P = 0.0003) for current smokers. The proportion of adenocarcinomas (36.8%) was almost the same as that of squamous cell carcinomas (38.5%), with a ratio 1:1.05.


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Table I. Characteristics of study population
 
There were no significant differences in the frequency of GSTM1 gene deletion among age groups (by decade) in either the case group (20–39%) or the controls (16–30%), except for controls aged 60–69 years, in whom the frequency of GSTM1 null genotype was 4.2%, significantly lower than that in other age groups of controls. We did not observe significant differences of prevalence of GSTM1 gene deletion by gender in either the case group or the control group. However, the frequency of GSTM1 null genotype was higher in males in the case group (31.8%) than in male controls (17.2%), with borderline significance (P = 0.051). There was no such difference in female subjects.

Table IIGo shows the association between lung cancer and GSTM1 polymorphisms. The null genotype was detected in 37 of the 117 in the case group (31.6%), but in only 24 of the 120 controls (20%); the OR was 2.10 (95% CI 1.07–4.11) after adjustment for age, gender and lifetime smoking history (pack-years), suggesting that the null genotype of GSTM1 was associated with lung cancer. In further analysis of the association between histological types of lung cancer and GSTM1 polymorphisms after adjustment for age, gender and lifetime smoking history, adenocarcinoma was not significantly related to GSTM1 null genotype (OR 1.95, 95% CI 0.81–4.66), but squamous cell carcinoma was (OR 2.98, 95% CI 1.09–8.19). Small cell carcinoma had the highest OR (3.16) (95% CI 0.74–13.60) of all histological types, but the OR did not reach significance, possibly because of the small sample size. When squamous cell carcinoma and small cell carcinoma were combined into a classification of Kreyberg I, the association was still significant with an OR of 2.60 (95% CI 1.06–6.38). No significant association was found in the group of other histological types combined.


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Table II. Odds ratiosa of lung cancer in relation to GSTM1 genotype in African-Americans
 
In the analysis of lung cancer risk and smoking, we did not find any significant association between GSTM1 null genotype and lung cancer in ex-smokers (OR 4.06, 95% CI 0.42–39.34), current smokers (OR 1.36, 95% CI 0.66–2.81) or those who had ever smoked (OR 1.75, 95% CI 0.89–3.42). However, when we analyzed the combined effect of GSTM1 null genotype and smoking status, the subjects who smoked and bore the GSTM1 null genotype had a higher risk of lung cancer (OR 8.19, 95% CI 2.35–28.62) in comparison with controls who never smoked and bore the wild-type genotype.

We also examined the association between GSTM1 polymorphism and lung cancer risk by cumulative smoking history among those who had ever smoked. Smoking data were stratified into two categories divided at a cut-off value of 30 pack-years, which was the mean of lifetime smoking history for those in the control group who had ever smoked. There was no significant association between GSTM1 null genotype and lung cancer risk in subjects who had smoked for <30 pack-years (OR 1.04, 95% CI 0.40–2.67). However, the association between GSTM1 deletion and lung cancer was significant in subjects who had smoked for >=30 pack-years, with an OR of 4.35 (95% CI 1.16–16.23) (Table IIIGo). Because the GSTM1 null genotype was related to the risk of lung cancer among those who had smoked for >=30 pack-years, we examined this association in each histological type. Table IIIGo shows that the association between lung cancer and GSTM1 gene deletion was greater among heavier smokers than among lighter smokers in all histological types. However, this association was significant only in squamous cell carcinoma (OR 6.26, 95% CI 1.31–29.91) or Kreyberg I (combined squamous cell carcinoma and small cell carcinoma) (OR 5.90, 95% CI 1.34–25.99) among those who had smoked for >=30 pack-years. We also stratified the data at the cut-off value of 35 pack-years and 40 pack-years, as has been done in other studies (7,15,19), to analyze the association between lung cancer and GSTM1 polymorphism, and found that the results were not changed (data not shown). In the smokers of <35 pack-years or <40 pack-years, there was no significant association between lung cancer and GSTM1 polymorphism. In the smokers of >=35 pack-years, however, one of 24 controls (4.2%) had the GSTM1 null genotype in comparison with 17 of 52 cases (32.7%), with an OR of 11.99 (95% CI 1.39–103.59). None of the 19 smokers of >=40 pack-years in the control group had the null genotype, but 16 of 45 cases (35.6%) had the GSTM1 gene deletion.


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Table III. Odds ratiosa of lung cancer and its histological types by GSTM1 polymorphism and stratified lifetime smoking historyb
 
Table IVGo shows the result of analysis of the combined effect of GSTM1 polymorphisms and lifetime smoking history (pack-years) on lung cancer risk. The risk of lung cancer increased with increasing pack-years of smoking (P-value < 0.0001 for trend). The OR for those who had smoked for >=30 pack-years and bore the GSTM1 null genotype was 28.29 (95% CI 5.49–145.87), compared with non-smokers bearing the wild-type GSTM1 gene, although the point estimate is very unstable due to the small number of subjects in certain subgroups.


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Table IV. Combined effect of lifetime smoking history(pack-years) and GSTM1 polymorphisms on lung cancera
 
Removing the 12 cases whose information was obtained from the Harlem Hospital Tumor Registry alone had no effect on the results of the analysis.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our results indicate that the GSTM1 null genotype is associated with lung cancer in African-Americans, especially for patients with squamous cell carcinoma who smoke heavily. This is the first time this association with histological type and smoking has been identified in African-Americans; the results are consistent with previous studies in other ethnic populations (37,19). Compared with Caucasians, African-Americans have a lower prevalence of the GSTM1 null genotype (15) and consume fewer cigarettes per day (20). The higher incidence and mortality rate from lung cancer among African-Americans suggests, however, that they may be more sensitive than Caucasians to carcinogenesis related to cigarette smoke (20,21). Thus, African-Americans may be at increased risk of lung cancer if they lack the GSTM1 gene and are exposed to carcinogens such as those found in cigarette smoke. It is also possible that in African-Americans GSTM1 is associated with other gene polymorphisms involved in the carcinogenic process, or that GSTM1 is linked to one or more key genes in African-Americans only. There is evidence that associations between metabolic gene polymorphisms and cancer may vary with race (22) and that genetic linkages between loci may also be race specific.

The prevalence of the GSTM1 null genotype in African-Americans varies between studies, with values of 35% (North Carolina; 23), 31% (California; 24), 28% (Tennessee; 25), 27% (California; 15) and 23% (Texas; 16) having been reported. The frequency of GSTM1 gene deletion found in the control population of this study (20%) is lower than that in most of these studies, but is relatively close to that in the control population in Texas (23%). The frequency of GSTM1 gene deletion in the case population of this study (31.6%) is higher than that found in two of the above studies, 27.8% (California; 15) and 22.2% (Texas; 16). The reason for these differences is not straightforward. Because an internal control (ß-globin) was co-amplified in every sample and the mixed samples were examined together, our observations are not likely to be due to variability in laboratory techniques. The observed differences among study populations may be attributable to chance, differences in sampling methods and/or regionally distributed genetic variation among AfricanAmericans due to different degrees of population admixture between Africans and Caucasians in different regions of the USA. Similar geographic differences within the USA have been seen for frequencies of CYP1A1 gene restriction fragment length polymorphisms (26). The latter explanation is supported by a study showing 22% GSTM1 gene deletion in the population of Nigeria (27).

To date, there have been two publications on the association between GSTM1 polymorphisms and lung cancer in African-Americans (15,16). London et al. (15) conducted a population-based case–control study in Los Angeles County and did not find an association between lung cancer and GSTM1 polymorphisms in African-Americans. The authors, however, did observe an association between lung cancer and GSTM1 null genotype among those, including Caucasians and African-Americans, who had smoked for <40 pack-years. Another hospital-community case–control study carried out in Texas (16) found no evidence that GSTM1 polymorphism alone was associated with lung cancer or modified the effect of smoking in the development of lung cancer in African-Americans. There are several possible reasons for the discrepancy between these results and ours. First, the sources of the study populations differed between these studies. The lung cancer cases in our study were newly diagnosed and histologically confirmed. Though the controls in our study were patients with many kinds of diseases other than cancer, including some lung diseases, previous studies have confirmed that the frequency of GSTM1 gene deletion in patients with lung diseases was similar to that of a healthy population (19). Even though there were some controls with diseases associated with GSTM1 polymorphism, such as pulmonary asbestosis (28) and familial adenomatous polyposis (29), this would decrease, not increase, the association between GSTM1 polymorphism and lung cancer because these patients have a higher frequency of GSTM1 null genotype than healthy controls (28,29). Secondly, these studies differ in the distributions by histological type in the case group. In our study, squamous cell carcinoma of the lung accounted for a greater proportion of the cases (38.5%) than did adenocarcinoma (36.8%) or other histological types, and is associated with GSTM1 polymorphism. In the study of London et al., squamous cell carcinoma of the lung accounted for a low proportion (24%) and adenocarcinoma for a high proportion (35%) of the cases, though these proportions included Caucasians and African-Americans. In addition, as mentioned above, regional variations in the prevalence of GSTM1 polymorphisms among African-Americans may also play some role in these studies. We have to stress, however, that the small sample size gives very unstable point estimates when conducting stratified analyses.

In the analysis of the association between lung cancer and GSTM1 polymorphism as influenced by lifetime smoking history, we chose 30 pack-years, not 40 pack-years as in other studies (7,15,19), as the cut-off value for stratification because African-Americans consume fewer cigarettes than Caucasians (20), and this value was the mean of lifetime smoking history in our smoking controls. Our findings that there was an association between lung cancer and the GSTM1 null genotype among smokers of >=30 pack-years, but not in smokers of <30 pack-years, and that the risk of lung cancer increased with lifetime smoking history, are similar to the findings of some previous studies (7,19). Many epidemiological studies have demonstrated that squamous cell carcinoma of the lung and small cell carcinoma of the lung, or Kreyberg I cancers, are more closely associated with cigarette smoking than adenocarcinoma of the lung, and patients with squamous cell carcinoma smoked, on average, more cigarettes than those with adenocarcinoma (20). Recent studies have shown an association between lung cancer, GSTM1 polymorphism and lifetime smoking history (pack-years), only in relation to squamous cell carcinoma of the lung (5,7,15,19). These results differ from those of earlier studies revealing the association only in adenocarcinomas (3,4,8). In our study, patients with squamous cell carcinoma of the lung had higher mean pack-years (46 pack-years) than those with adenocarcinoma (34 pack-years), and the association between lung cancer and GSTM1 polymorphism was found in squamous cell carcinoma of the lung but not in adenocarcinoma of the lung; heavy smokers with squamous cell carcinoma of the lung had a greater risk. These results further indicate that GSTM1 may play an important role in detoxification of carcinogens from cigarette smoke and modify the effect of cigarette smoke in the development of lung cancer, particularly in squamous cell carcinoma of the lung. Studies in other ethnic populations (5,7,19) have found similar results. Cigarette smoke contains many carcinogens such as PAHs. By glutathione conjugation, GSTM1 can detoxify many carcinogens from cigarette smoke and prevent them from forming DNA adducts, thereby modifying the effect of cigarette smoking in the development of lung cancer. Research studies have shown that PAH–DNA adduct levels are higher in smokers than in non-smokers (30), and that they are higher in subjects with the GSTM1 null genotype than in those with the GSTM1 wild-type genotype (31). Epidemiological studies have also confirmed that lung cancer is associated with cigarette smoking, and the risk increases with lifetime smoking history expressed in pack-years (1). It is conceivable that if an individual is exposed to more cigarette smoke than can be detoxified by GSTM1, excess carcinogens from cigarette smoke will fail to be detoxified and their metabolites will contribute to initiation of carcinogenesis. London et al. (15) also found an association between lung cancer and the GSTM1 null genotype among those, including Caucasians and African-Americans, who had smoked for <40 pack-years but not among those who had smoked for >=40 pack-years. The authors, however, did not mention whether this association also existed in African-Americans.

Other genetic polymorphisms, e.g. in CYP1A1, may influence the association between GSTM1 polymorphisms and lung cancer (12,32). Our analysis of the relationship between combinations of CYP1A1 and GSTM1 polymorphism and lung cancer risk is in progress. As in the case of studies in other ethnic groups, studies in African-Americans on the association between GSTM1 polymorphisms and the risk of lung cancer present differing results, which suggests that more and larger-scale molecular epidemiological studies will need to be conducted to examine this association further.


    Notes
 
8 To whom correspondence should be addressed Email: jf24{at}columbia.edu Back


    Acknowledgments
 
This study was supported by NIH grants CA01643, ES06831 and ES08363.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received January 28, 2000; revised July 18, 2000; accepted July 27, 2000.