Associations between carcinogenDNA damage, glutathione S-transferase genotypes, and risk of lung cancer in the prospective Physicians Health Cohort Study
Frederica P. Perera5,
LaVerne A. Mooney,
Meir Stampfer1,
David H. Phillips2,
Douglas A. Bell3,
Andrew Rundle,
Stan Cho,
Wei-Yann Tsai,
Jing Ma1,
Anne Blackwood4 and
Deliang Tang
Joseph L.Mailman School of Public Health, Columbia University, New York City, NY 10032,
1 Channing Laboratory, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA,
2 Institute of Cancer Research, Haddow Laboratories, Cotswold Road, Sutton, Surrey SM2 5NG, UK,
3 National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 and
4 Center for Clinical Epidemiology and Applied Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
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Abstract
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DNA damage from polycyclic aromatic hydrocarbons (PAH) and other aromatic/hydrophobic compounds has been implicated in casecontrol studies as a risk factor for lung cancer, as have common polymorphisms in the glutathione S-transferase (GST) genes involved in carcinogen detoxification. However, their joint effects have not been evaluated in prospective studies, leaving open questions about predictive value of these biomarkers. In this matched casecontrol study nested within the prospective Physicians Health Study, we evaluated whether biomarkers measured in white blood cells (WBC) significantly predicted risk, alone and in combination, after controlling for level of smoking. The biomarkers reported here are aromatic/hydrophobicDNA adducts and polymorphisms in genes coding for the GSTM1 and GSTP1 enzymes. Our study population was composed of 89 cases of primary lung cancer and 173 controls, matched in a 1:2 ratio on smoking, age and duration of follow up. Adducts were measured in WBC DNA by the nuclease P1-enhanced 32P-post-labeling method. Genotypes (GSTM1 null versus non-null and GSTP1 Val versus GSTP1 Ile) were determined by genomic amplification and restriction fragment length polymorphism analysis. Among current smokers, adducts were significant predictors of lung cancer risk (after adjusting for GST genotypes, OR = 3.10, 95% CI 1.07, 9.01). The combined GSTM1 null/GSTP1 Val genotype was associated with lung cancer overall and especially among former smokers, before and after adjusting for adducts (OR for former smokers = 4.21, CI 1.08, 16.41; adjusted OR = 4.68, CI 1.17, 18.71). Among cases only, adducts were significantly higher among current or former smokers with the GSTM1 non-null/GSTP1 Ile genotype. The two risk factors (adducts and genotypes) appear to be independent predictors of risk. The findings underscore the complex and important role of biological susceptibility as a determinant of risk from carcinogens found in tobacco smoke and other environmental compounds.
Abbreviations: BPDE, B[a]P-diolepoxide; DRZ, diagonal radiation zone; GST, glutathione S-transferase; Ile, isoleucine; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NSCLC, non small cell lung carcinoma; PAH, polycyclic aromatic hydrocarbons; PCR, polymerase chain reaction; PHS, Physicians Health Study; RFLP, restriction fragment length polymorphism; SCLC, small cell lung carcinoma; Val, valine; WBC, white blood cells
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Introduction
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Lung cancer is the leading cause of cancer deaths in the USA in men and women, with 170 000 new cases annually (1). Active cigarette smoking, passive smoking, various occupational exposures, and carcinogens in heavily polluted air are causally related to lung cancer in humans (2,3). PAH, the aromatic amine 4-aminobiphenyl, heterocyclic amines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acrolein, acrylonitrile, ethylene oxide and many other DNA-damaging agents are among the 50 known carcinogens in tobacco smoke (3,4). PAH and other aromatics are also found in ambient and indoor air and in the diet (57). Experimental research has demonstrated that PAH and many other carcinogens form covalent DNA adducts that may lead to mutation in targets such as the p53 tumor suppressor gene and, ultimately, to cancer (811). A number of molecular epidemiologic (12,13), and experimental studies (14) have shown a good correlation between PAH and aromaticDNA adducts in blood and lung tissue from the same individuals. Several studies have found a higher prevalence or elevated concentrations of PAH/aromaticDNA adducts in WBC or lung tissue of cancer cases compared with controls (12,1519). These earlier findings suggested that the propensity to activate and bind carcinogens to DNA might be a risk factor in lung cancer.
Glutathione S-transferase (GST) consists of a super-family of Phase II enzymes that catalyze the conjugation of reduced glutathione with electrophilic compounds, including many environmental mutagens and carcinogens (20). The currently identified cytosolic GSTs are categorized into four main classes,
, µ,
and
, based on biochemical characteristics (21). Human
, µ and
families contain multiple genes, while the
family consists of a single gene, GSTP1. The class µ (M1) and
(P1) genes have multiple substrates, including epoxides of PAH such as B[a]P-diolepoxide (BPDE), acrolein and other unsaturated carbonyls generated by lipid peroxides and oxidative damage to DNA (2124). GSTM1 is most strongly expressed in the liver and to a much lower extent in the lung (25). GSTP1 is widely expressed in human epithelial tissue, and is the dominant GST present in the lung (26). GSTM1 is deleted in about half of Caucasians (27). Both GSTM1 and GSTP1 are expressed in lymphocytes, with P1 being expressed at higher levels (28). A coding sequence polymorphism in GSTP1, an A
G transition in nucleotide +313, has been identified that results in a change in codon 105 from isoleucine (Ile) to valine (Val) in the hydrophobic binding site and impacts catalytic efficiencies (29). The effect of the 105 Val allele appears to differ by substrate. Compared with the GSTP1 Ile allele, the GSTP1 Val allele has decreased activity towards 1-chloro-2,4-dinitrobenzene but greater activity towards PAH diolepoxides (3032).
Prior data on the associations between the GST polymorphisms and cancer risk have been conflicting. However, most studies show a modest effect of GSTM1 null on lung cancer (25,33,34). The 105 Val P1 allele has been associated with increased risk of lung and upper aerodigestive tract cancers in some, but not all, studies (25,35). A recent report suggested that the combination of GSTM1 null/P1 Val polymorphisms conferred excess risk of lung cancer in younger patients (36). Reports of the association between GSTM1 and P1 and DNA adducts have also been mixed, with results varying by type of tissue, laboratory methods, and specific adducts measured (37) (see Discussion).
We have conducted a matched casecontrol study nested within the Physicians Health Prospective Cohort Study (PHS) (38) to determine the relationship between a number of biological markers measured in enrollment blood samples from healthy individuals and subsequent risk of lung cancer. We have previously reported a significant relationship between lung cancer risk and polycyclic aromatic hydrocarbon (PAH) and other aromatic/hydrophobicDNA adducts in current smokers (39). Here we have evaluated the separate and joint effects of DNA adducts and polymorphisms in glutathione S-transferase M1 and P1. Our hypothesis was that, after controlling for cigarette smoking as the major exposure source, GSTM1 null/GSTP1 Val genotypes and aromatic/hydrophobic adducts at baseline would significantly predict risk, consistent with the cases having greater biological susceptibility to multiple carcinogens.
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Materials and methods
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The parent (PHS) study
The PHS was a randomized trial of the effect of aspirin on cardiovascular mortality and the effect of ß-carotene on cancer incidence. This investigation was conducted among 22 071 USA male physicians, nearly all of whom were Caucasian. Subjects with a history of cancer (except for non-melanoma skin cancer) were excluded from the study. The overall smoking distribution in the PHS was 39% ex-smokers, 11% current smokers and 50% nonsmokers. All subjects were asked to donate a blood sample at initial enrollment; and roughly 75% complied. There were no notable differences between the `blood subgroup and the whole cohort with respect to demographics. There was virtually no loss to follow-up of the cohort: 100% were followed up for vital status, and >99% were followed up for nonfatal outcomes. It is likely that few, if any, cases were missed given the nature of the population and the tracking system in place. Between August 1982 and December 1984, 14 916 baseline blood samples (two 4 ml tubes of plasma and one 4 ml tube of whole blood) were collected from physicians who subsequently entered the PHS study and were randomly assigned to one of four groups (aspirin and ß-carotene treatment, aspirin, ß-carotene, or neither treatment). The samples were coded and stored at 80°C.
Questionnaires regarding their health history were completed by the physicians at entry and at 2, 6, 12, 24, 36, 48 and 60 months. Follow-up after 5 years consisted of yearly questionnaires and postcard inquiries every six months regarding heart disease or cancer diagnosis. Smoking history was obtained from each physician at enrollment . This history included smoking status (never, former (had smoked regularly), current (smoking at time of enrollment), and current cigarettes/day) as well as status of cigar and pipe smoking.
The nested casecontrol study
In the present nested casecontrol study, a panel of biological markers was measured in baseline blood samples that were collected at the outset of the PHS (38). In addition to the frozen whole blood and plasma specimens, an extensive database was available on each study participant in the nested casecontrol study, including serial questionnaire data, medical record review, pathology reports, and autopsy reports for the cancer cases. Data on age, tobacco habits and other variables were extracted from questionnaires.
A total of 89 lung cancer cases was documented over a 13 year period (19821995) in the subset of the cohort with blood samples. For the cases, the date of first hospital admission for lung cancer or first documented visit for symptoms related to the diagnosis of lung cancer was regarded as the incident date. The histologic type of cancer was obtained by the PHS staff from pathology reports or, for two subjects, from death certificates. Upon identifying each new case, the PHS contacted the patients hospital and requested pathology reports, medical records, and samples of lung tumor and tumor adjacent tissue removed at the time of surgery. Two controls were matched to each incident case at the time of diagnosis. The controls were cohort members without a prior diagnosis of cancer (excluding non-melanoma skin cancer) prior to the date of matching. Matching of cases and controls was based on age (±1 year), length of follow-up to diagnosis of case (+6 months), smoking status at enrollment (never used tobacco regularly; former smoker; current smoker), and, for current smokers only, cigarettes smoked per day (119, 2039, 40 or more cigarettes per day). Cigarette smoking data and adduct data were not available for one (2%) case and two (1%) controls, and two (2%) cases and 13 (7.5%) controls, respectively.
Analysis of aromatic/hydrophobicDNA adducts
Whole blood aliquots were shipped by the PHS investigators to Columbia University, where DNA from total WBC was isolated by the standard chloroform DNA extraction procedure. The DNA was sent to the Institute of Cancer Research (UK) for analysis of aromatic adducts by nuclease P1-enhanced 32P-post-labeling as previously described (40). All analyses were carried out on coded samples, and all investigators were blinded to case/control and treatment status. Samples from matched cases and controls were handled identically, shipped in the same batch, and assayed in the same analytical batch. The order of analysis was randomly determined within each casecontrol triad. Specimens were analyzed in triplicate on different days and the mean adduct level was determined for each individual. For each batch of samples run sequentially, a positive control, consisting of B[a]P- or benzo(g)chrysene-modified DNA, was included. Batch effects (systematic variation between analytical runs) were assessed by ANOVA and were not statistically significant.
In general, the 32P-post-labeling method with nuclease P1 digestion is efficient for most PAH adducts but not for many aromatic amine adducts (41). Under controlled conditions using a BPDE-modified DNA, the nuclease P1 enhancement method has been shown to recover 93% of adducts (7). As in prior studies, total DNA adduct levels were measured in the diagonal radioactive zone (DRZ) area of the thin layer chromatography (TLC) plates and were considered primarily to represent PAHDNA and other aromatic/hydrophobic adducts resistant to nuclease P1 digestion (39). The method provides a summary measure of a complex mixture of adducts present in the post-labeling chromatograms. Tobacco smoke is considered to be the dominant source of adducts detected. Prior analyses of various tissues (blood, lung, cervix) have associated adducts in the DRZ with exposure to tobacco smoke (42).
Analysis of GSTM1 genotype
To assess individual GSTM1 genotype, DNA was extracted from blood leukocytes and analyzed by polymerase chain reaction (PCR) as previously described (27). The primers used in the PCR mix were G5, 5'GAA CTC CCT GAA AAG CTA AAG C; G6, 5'GTT GGG CTC AAA TAT ACG GTG G.
Analysis of GSTP1 genotype
The GSTP1 (ile105val) genotype was determined by use of the PCRRFLP method as described previously (20,26). Briefly, genomic DNA (50 ng) was added to a PCR mix of GSTP1 primers 2306F (5'-GTA GTT TGC CCA AGC TCA AG) and 2721R (5'AGC CAC CTG AAG GGT AAG) (15 pmol each), and other PCR reagents (26). PCR products were digested overnight with the restriction enzyme Alw26I, which distinguishes between the restriction sites on the Ile allele (ACA TCT) and the Val allele (ACG TCT). For all genotype analyses, laboratory personnel were blinded to sample status; photographs were interpreted by at least two independent readers; and ~10% of samples were tested a second time as a quality control measure. Subjects were characterized as homozygous or heterozygous for the Val or Ile alleles. For purposes of the final statistical analysis, subjects were classified as Val (Val/Val or Val/Ile) or Ile (Ile/Ile).
Statistical analysis
Adducts were log transformed to stabilize the variance and normalize the distribution. Analysis of variance (ANOVA) was applied to determine whether smoking status was associated with adduct levels, across strata of genotype. In order to take advantage of the dependence between cases and matched controls, the paired t-test was used to test for differences in adduct means between cases and controls (using the mean of the two controls) within each of the genotype (GSTM1 and GSTP1) strata. To account for matched factors, a conditional logistic model was used to generate odds ratios and 95% confidence intervals (43) for adducts and for the genotypes, alone and combined. Adducts were considered as a dichotomous variable (elevated adducts were defined as greater than the median adduct level in controls).
As described above, in the PHS study, enrollees were randomly assigned to aspirin and ß-carotene treatment groups after donating a baseline blood sample. Because ß-carotene and aspirin have been reported in some studies to affect lung cancer risk, we included each treatment in models that examined the relationship of adducts or genotypes to cancer. Odds ratios were also calculated for the main histologic groups: small cell lung carcinoma (SCLC) and non-SCLC (NSCLC). The small number of cases in our population limited the analysis by each histologic type.
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Results
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Demographic and histologic characteristics of the study population have been reported previously (39). Detailed results on adducts as a single biomarker have been reported, including the finding that among the current smokers there was a significant increase in mean adduct level of the cases compared with the controls (11.04 versus 5.63/108, P = 0.03) (39,44). In our study population, aromaticDNA adduct levels in relation to GSTM1 and GSTP1 genotypes and smoking status are presented in Table I
. After stratifying on smoking, the combined GSTM1/P1 genotype was associated with higher aromaticDNA adduct levels among cases who were either current or former smokers (P < 0.05), but not among nonsmoker cases or controls. The associations between the individual genotypes and adducts were not significant; however, among former smokers that for GSTM1 was of borderline significance (P = 0.05) (data not shown).
By conditional logistic regression, elevated DNA adducts were significantly associated with lung cancer risk among current smokers before (OR = 2.98,CI 1.05, 8.42, P = 0.04) and after adjusting for both GST polymorphisms, singly and combined (OR adjusted for the combined GSTM1 null/GSTP1 Val genotype = 3.11, CI 1.07, 9.10) (Table II). A similar relationship was not seen among former smokers or never smokers. Controlling either for cigarettes smoked per day (CPD) by the current smokers, for cigar and pipe smoking, or ß-carotene or aspirin treatment did not alter the relationships between adducts and risk. As previously reported, odds ratios for adducts did not vary by major histologic group (NSCLC versus SCLC) or length of follow-up (<3 years versus
3 years).
The GSTM1 null and GSTP1 Val genotypes were individually not significantly associated with lung cancer risk. However, the combined GSTM1 null/GSTP1 Val genotype was associated with lung cancer overall before and after adjusting for adducts (adjusted OR = 2.44, CI 1.09, 5.46) and most strongly among former smokers (adjusted OR = 4.68, CI 1.17, 8.71) (Table II). Controlling for cigarettes smoked per day by the current smokers, or for ß-carotene or aspirin treatment did not alter the relationships between the genotypes and risk. There were no significant interactions between genotypes and adducts on risk of lung cancer. The OR for the combined genotype was significant for NSCLC (OR = 2.66, CI 1.09, 6.49) but not for SCLC (OR = 1.02, CI 0.15, 6.84).
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Discussion
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We previously reported that adducts in WBC predicted lung cancer among current smokers. Here we report that the relationship remains significant after controlling for the GSTM1 and GSTP1 genotypes, individually and combined. The GSTM1 null/P1 Val genotype was also an independent predictor of lung cancer risk (overall and in former smokers). Adduct levels measured in WBC were not a significant confounder or mediator of the relationship between GST genotypes and lung cancer risk. In contrast to adducts, the odds ratio for GSTM1 null/P1 Val varied by the major histologic groups, being significant only for NSCLC.
The finding that, after controlling for GST genotype, aromaticDNA adducts in WBC predict lung cancer risk is biologically plausible since adducts are on the pathway to mutation and cancer (10,17,45,46). Moreover, although the relationship between WBC adducts and tissue adducts may vary by carcinogen and target site, significant correlations have been seen between PAH and aromatic adducts in WBC and those in lung tissue (1214,16). There is evidence that certain individuals are inherently more susceptible to DNA damage and cancer from environmental carcinogens, due to increased metabolic activation of carcinogens, decreased detoxification, and/or decreased DNA repair (4751). The most likely explanation for our observing the association in current smokers only probably reflects the fact that the predominant source of adducts detected by the method used is tobacco smoking. In theory, current smokers who subsequently become cases experience higher levels of DNA damage than those who remain free of cancer; and the casecontrol difference in adducts would be most evident in the presence of ongoing challenge via active smoking.
This study showed a significant effect of polymorphisms in phase II enzymes (GSTM1 null/P1) on lung cancer risk, especially for NSCLC. This observation is biologically plausible since the substrates for M1 and P1 include a variety of carcinogens in tobacco smoke and other environmental mixtures. These include acrolein, epoxides of PAH such as BPDE and other DNA damaging agents (2124). The finding is consistent with the literature in that many studies show an association between GSTM1 null and lung cancer risk (34). As mentioned, Ryberg and colleagues reported that the GSTP1 Val genotype was associated with lung cancer (35). The combined genotype has been little studied; however, a preliminary report suggests that the combined GSTM1 null/P1 Val genotype was associated with risk of lung cancer in subjects <55 years of age (36). Another study found no association (52).
Overall and among the controls, adduct levels were not significantly different in the various GST genotype strata. However, among the cases, aromatic adducts were significantly higher in current and former smokers with the GSTM1 non-null/GSTP1 Ile genotype, rather than the GSTM1 null/GSTP1 Val genotypes which we found to be associated with lung cancer. Results of studies of the association between GSTM1 and P1 and adducts have been inconsistent (37). However, our findings on the association between GST genotypes and aromaticDNA adducts are in contrast with much of the literature, where a number of studies of mononuclear lymphocytes or lung tissue have reported higher adducts in individuals with the GSTM1 null genotype and/or the GSTP1 Val genotype (5356). However, WBC PAHDNA adducts were reported in one study to be lower in subjects with the GSTM1 null genotype (57). In lung cancer patients who were current smokers, a significant association was seen between the 105 Val allele and aromaticDNA adducts in lung tissue, measured by the 32P-post-labeling method (35). However, our finding that adducts in WBC were higher in the GSTP1 Ile subjects is consistent with enzyme studies suggesting that the GSTP1 Ile genotype is less efficient at detoxifying certain PAH diol epoxides (22,31,32). Specifically, the residue at 105 appears to define the geometry of the hydrophobic substrate-binding site such that enzyme activity with valine at 105 is greater towards larger substrates such as PAH epoxides; whereas activity is lower towards smaller substrates like 1-chloro-2, 4-dinitrobenzene (29). Levels of PAHDNA adducts measured by immunoassay were also significantly higher in cord blood of newborns with the combined CYP1A1 Msp1/GSTP1 (Ile/Ile) genotype, compared with GSTP1 Val/Val newborns who lacked the CYP1A1 restriction site (58). Thus, the literature is inconsistent on these associations. The results of our regression analysis suggest that the two risk factors identified here (adducts and GSTM1 null/GSTP1 Val genotypes) are independent factors for increased cancer risk, suggesting that the polymorphic GST genotypes may be affecting cancer risk predominantly via their action on substrates other than PAH and other aromatics detected by the 32 P-post-labeling assay in WBC.
A major strength of this study is the nested casecontrol design, which avoids uncertainty about time order and reducing error and bias in recalling past exposure. To date, this study and two prior ones of aflatoxin and liver cancer (5961) are the only studies to evaluate the predictive value of carcinogenDNA adducts within a prospective cohort design. However, there are a number of limitations. Given the nature of the 32P-post-labeling method, we are unable to specify the exact composition of the adducts for subtype analysis. Furthermore, we did not have data on changes in smoking post enrollment, which may have biased our results toward the null since controls with high enrollment levels of adducts may have subsequently reduced both their adduct levels and lung cancer risk by quitting. It is possible that unmeasured differences in smoking habit (brand, number of puffs etc) might explain our results; we were able to control only for differences in CPD. The study was limited by small numbers. This precludes definitive conclusions regarding interactions between aromatic/hydrophobic adducts with polymorphisms in detoxifying genes or biomarkerdisease relationships stratified by histologic type of cancer. In spite of our limited sample size, a trend of increased risk of lung cancer with the GSTM1 null and GSTPI Val allele was seen, when these genes were considered both singly and in combination. A final limitation is that we cannot necessarily assume that adducts measured in men at older ages are representative of those present at earlier ages when, presumably, critical initiating events would have occurred. This is particularly true for individuals whose environmental exposure has changed significantly over time, as in former smokers, particularly because the assay was performed on total leukocyte DNA, rather than on the long lived lymphocytes. However, being constitutional, the genotypes studied here do not have the same limitation.
In conclusion, in the present study elevated aromatic/hydrophobic carcinogenDNA adducts in WBC were significant predictors of lung cancer risk in current smokers, after adjusting for GST genotypes. The double variant (GSTM1 null/P1 Val) genotype independently predicted risk of lung cancer, overall and in former smokers, implicating multiple environmental carcinogens that are detoxified by these enzymes.
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Notes
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5 To whom correspondence should be addressed at: Division of Environmental Health Sciences, Joseph L. Mailman School of Public Health, Columbia University, New York City, NY 10032, USA Email: fpp1{at}columbia.cdu 
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Acknowledgments
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The authors gratefully acknowledge the valuable contribution of Luis Ortega, MD, formerly at Columbia University; Kathleen O Toole, MD, of Columbia University, and Yanzhi Hsu, PhD, of Columbia University. This work was supported by a grant from the National Cancer Institute, National Institutes of Health, #5RO1 CA 53772, `Molecular Epidemiology of Lung Cancer: a Nested CaseControl Study.
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Received January 23, 2002;
revised May 3, 2002;
accepted May 8, 2002.