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Division of Environmental Health Sciences, Joseph L. Mailman School of Public Health, Columbia University, New York, New York 10032 [D. T., L. A. M., Y. H., S. C., W-Y. T., F. P. P.]; Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, United Kingdom [D. H. P., K. J. C., M. N. S.]; and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 [M. S., J. M.]
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ABSTRACT |
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Introduction |
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Lung cancer is the leading cause of cancer deaths in the United States in men and women. In 1999, 171,600 new cases were diagnosed (3) . Although active cigarette smoking is the major cause of lung cancer, passive smoking, various occupational exposures, and carcinogens found in heavily polluted air are also causally related to lung cancer in humans (4 , 5) . Tobacco smoke contains over 50 known carcinogens including BaP and other PAHs, aromatic amines such as 4-aminobiphenyl, heterocyclic amines, and the nicotine-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (5 , 6) . In addition to being major carcinogenic constituents of tobacco smoke, PAHs are found in ambient and indoor air because of emissions from vehicles, power plants, industrial sources, cooking, and heating. They are also present in the diet from grilling or broiling of food and from atmospheric deposition (7, 8, 9) .
Experimental research has demonstrated that PAHs, like many carcinogens, exert their effects by binding covalently to DNA to form adducts that may lead to mutation and, ultimately, to cancer (10, 11, 12) . Although the relationship between adduct concentrations in blood and target tissues such as the lung has not been conclusively established, a number of molecular epidemiological studies (13 , 14) and experimental studies (15) have shown a good correlation between PAH- and aromatic-DNA adducts in blood and lung tissue from the same individuals. Thus, as a biomarker, adducts have the theoretical advantage of reflecting chemical-specific genetic damage that is mechanistically relevant to carcinogenesis. Supporting molecular evidence that DNA damage from PAHs may play an important role in lung cancer has come from the observation that the P53 tumor suppressor gene is mutated in 40–50% of lung tumors, and the pattern of p53 mutations is consistent with the type of DNA adducts and mutations induced experimentally by BaP (16) .
Carcinogen-DNA adducts, including aromatic adducts such as PAH-DNA, can be quantitated in human tissue by the 32P-postlabeling method (9 , 17) , by immunoassays (18 , 19) , and by physical/chemical methods (20) . Although not all of the studies have been consistent, a number have found a higher prevalence or elevated concentrations of these PAH/aromatic-DNA adducts in WBCs or lung tissue of cancer cases compared with controls (13 , 18 , 20 , 21) of smokers compared with nonsmokers (22, 23, 24, 25, 26) and of smokers sampled before and after smoking cessation (27) . These earlier findings suggested that the propensity to activate and bind carcinogens to DNA might be a risk factor in lung cancer.
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Materials and Methods |
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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 6 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 CPD] as well as status of cigar and pipe smoking.
The Nested Case-control Study.
In addition to the frozen whole blood and plasma specimens, an extensive database was available on each study participant in the nested case-control 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 were documented over a 13-year period (1982–1995) 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 histological 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 patient’s 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 nonmelanoma skin cancer) before the date of matching. Matching of cases and controls was based on the following criteria: (a) age (± 1 year); (b) length of follow-up to diagnosis of case (± 6 months); (c) smoking status at enrollment: never used tobacco regularly, former smoker, current smoker; and (d) CPD (1–19, 20–39, 40+) for current smokers only.
A prior study had observed seasonal variation in DNA binding, possibly related to seasonal fluctuations in aryl hydrocarbon hydroxylase activity, with aryl hydrocarbon hydroxylase activity higher in July-October compared with November-June (13 , 28) . In the present study, cases and controls were not matched on season of blood drawing because most of the samples were drawn during the months of July through October. Cigarette smoking data and adduct data were not available for one case and two controls and two cases and 13 controls, respectively.
Analysis of Aromatic/Hydrophobic-DNA Adducts.
Whole blood aliquots were shipped by the PHS investigators to Columbia University, where DNA from total WBCs was isolated by the standard chloroform DNA extraction procedure. The DNA was sent to the Institute of Cancer Research (Belmont, United Kingdom) for analysis of aromatic adducts by nuclease P1-enhanced 32P-postlabeling as described previously (26)
. All of the analyses were carried out on coded samples, and all of the investigators were blinded as to case/control and treatment status. Samples from 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 case-control 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 BaP-modified or benzo[g]chrysene-modified DNA, was included.
In general, the 32P-postlabeling method with nuclease P1 digestion is efficient for most PAH adducts but not for many aromatic amine adducts (29) . Under controlled conditions using a BaP diol-epoxide-modified DNA, the nuclease P1 enhancement method has been shown to recover 93% of adducts (9) . In the present study, total DNA adduct levels were measured in the DRZ area of the TLC plates and were considered to primarily represent PAH-DNA and other aromatic/hydrophobic adducts resistant to nuclease P1 digestion (30 , 31) . The method provides a summary measure of a complex mixture of adducts present in the postlabeling chromatograms. Prior analyses of various tissues (blood, lung, and cervix) have associated adducts in the DRZ with exposure to tobacco smoke (32) .
Statistical Analysis.
Biomarker data were log transformed to stabilize the variance and normalize the distribution of DNA adducts. Arithmetic means are presented. ANOVA was applied to determine whether smoking status was associated (at a significance level of P 
0.05) with adduct levels. To take advantage of the dependence between cases and controls in the matched design of this study, the paired t test was used to test for differences in adduct means between cases and controls using the mean of the two controls. To determine the need to control for possible confounding by laboratory variability, batch effects (systematic variation between analytical runs) were assessed by ANOVA and were not statistically significant. To account for matched factors, a conditional logistic model was used to generate ORs and 95% CIs (33)
. Adducts were considered both as a dichotomous variable (high/low) based on the median level among controls and as a continuous variable. In the latter case, the OR represents the estimated increase in risk of lung cancer associated with a log unit increase in adducts/108 nucleotides.
As described above, in the PHS study, enrollees were randomly assigned to aspirin and ß-carotene treatment groups after donating a baseline blood sample. Unlike ß-carotene, aspirin has not been reported to affect lung cancer risk (34) .4 Nonetheless, we included each treatment in models that examined the relationship of adducts to cancer risk.
Another consideration was that cases diagnosed early in the study may be prevalent cases and that the presence of preclinical disease may alter biomarkers in unknown ways. Therefore, mean levels of biomarkers for cases and controls were compared by duration of follow-up (<3 years versus 
3 years) to determine whether there might be an effect of active, though asymptomatic, disease on biomarkers. Separate logistic regression models were run to compare ORs in subjects with a shorter versus a longer duration of follow-up.
ORs were calculated for the two major groups: SCLC versus NSCLC. The small number of cases in our population limited the analysis by each histological type.
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Results |
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provides the distribution of cases by specific histological type. Table 2
shows the distribution of subjects according to age, duration of follow-up, and smoking status. Arithmetic mean levels of aromatic DNA adducts by case/control and smoking status are presented in Table 3
. The arithmetic mean for all of the cases was 8.32 adducts/108 nucleotides, compared with 7.39/108 for all of the controls. Among the current smokers, there was an approximate doubling in arithmetic mean adduct level of the cases compared with the controls (11.04 versus 5.63 adducts/108; P = 0.03). No significant case-control difference was seen within the other two smoking categories. By ANOVA, mean adduct concentrations did not differ significantly between smoking categories overall. However, among the cases but not controls, there was a modest but nonsignificant decreasing trend in mean adduct level from current smokers to former smokers to never-smokers (Table 3)
. Controlling either for the number of CPD by the current smokers or for cigar and pipe smoking did not materially alter the relationships between cigarette smoking and adducts or between adducts and risk.
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and 5
). Tests for interaction between smoking status and carcinogen-DNA adducts (treated as either a dichotomous or a continuous variable) on lung cancer risk were not significant (P < 0.05) when smoking status was entered either as three categories (current, former, never-smokers) or as two categories (current and former smokers combined, never-smokers). Adding ß-carotene or aspirin to the model did not materially alter the ORs (OR/log unit increase in adduct concentration for current smokers in the ß-carotene treatment group, 2.14; CI, 0.99–4.62; P = 0.05; or for current smokers in the aspirin treatment group, 2.14; CI, 0.97–4.70; P = 0.06). This is consistent with the reported lack of an effect of ß-carotene and aspirin on lung cancer risk in this cohort (2)
.4
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There were no significant differences between mean levels of adducts in cases with SCLC and NSCLC or between the two corresponding groups of matched controls (Table 6)
. ORs for either continuous or dichotomous adducts did not vary by histological group or type.
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Discussion |
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The hypothesis that PAH adducts and other aromatic adducts in WBCs would predict lung cancer risk is biologically plausible for a number of reasons. First, adducts are on the pathway to mutation and cancer (1 , 10, 11, 12 , 19 , 20 , 35) . Second, previous findings from human (14 , 21) and experimental (15) studies indicate that WBC adducts measured by the same 32P-postlabeling procedure are correlated with those in lung tissue. Using this method to analyze samples from patients undergoing surgery for lung cancer, Wiencke et al. (21) noted a major adduct in WBCs and in noninvolved lung tissue that cochromatographed with radiolabeled (+)-anti-BaP diol-epoxide-N2-deoxyguanosine. They found a significant correlation between DNA adduct levels in the mononuclear WBCs and lung tissue (14) . Similarly, in an earlier study using an immunoassay to detect PAH-DNA adducts, Tang et al. (13) found a significant correlation between DNA adducts in WBCs and lung tissue from the same subjects. Third, biological plausibility is also supported by considerable evidence that certain individuals are inherently more susceptible to genetic damage and cancer from environmental exposures such as tobacco smoke (1 , 36, 37, 38 , 46) . Molecular epidemiological research has demonstrated significant interindividual variation in carcinogen-DNA binding among subjects with comparable exposure, suggesting that DNA adducts have the potential to identify persons with an enhanced response because of the nature of their metabolic/detoxification and DNA repair pathways (25 , 36 , 39, 40, 41, 42, 43) . Moreover, a number of studies have shown a relationship between cancer at various sites and mutagen sensitivity, tested by measuring induction of DNA adducts (44) .
Although not all of the case-control studies have been consistent, a number using ELISA or high-performance liquid chromatography/fluorimetry to measure PAH-DNA adducts have reported that DNA adducts are elevated in WBCs or lung tissue of lung cancer cases compared with controls (13 , 18 , 20 , 24 , 45) ; e.g., Tang et al. (13) found higher PAH-DNA adduct concentrations in WBCs of 119 cases compared with 98 controls after adjusting for amount of smoking, dietary PAH exposure, and other potential confounders. Although the difference was greatest in smokers, adducts were also higher in former smoker cases compared with former smoker controls (13) . Taken together, these findings are consistent with other evidence that some individuals are predisposed to genetic damage from PAH and thereby to lung cancer (37) .
In contrast to the case-control study by Tang et al. (13) that used an immunoassay to detect PAH-DNA adducts in cases and controls, the present nested case-control study using 32P-postlabeling did not observe case-control differences in adduct levels in former or never-smokers. A possible explanation is that the assay used in the present study measured a pattern of aromatic adducts (DRZ) predominantly associated with cigarette smoking (32) . Among current smokers, active smoking is likely to be the dominant source of aromatic adducts detected by the assay, and we were able to control this by matching and further adjusting for variation in amount of exposure via this route. However, given that the estimated half-life of DNA adducts in WBCs is 4 months (46) , among the former smokers, cell turnover and DNA repair would have reduced smoking-related adducts before blood sampling and analysis. Thus, in former and never-smokers, adducts are likely to reflect multiple background sources (environmental tobacco smoke, air pollution, and so forth) for which we were unable to control. Larger numbers of subjects are needed to test whether DNA damage from environmental exposures other than active smoking is predictive for lung cancer.
Case-control studies such as those cited above are by their retrospective nature limited in their ability to establish causality of environmental factors. A major strength of this study is the nested case-control 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 (47, 48, 49) are the only studies to evaluate the predictive value of carcinogen-DNA adducts within a prospective cohort design. However, there are a number of limitations. Given the nature of the 32P-postlabeling 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 after enrollment. It is possible that this may have biased our results toward the null because controls with high enrollment levels of adducts may have subsequently reduced both their adduct levels and lung cancer risk by quitting. Although it is unlikely that unmeasured differences in smoking habits (brand, number of puffs, and so forth) might explain our results, we were only able to control for differences in CPD. The limited number of cases precludes definitive conclusions regarding biomarker-disease relationships by histological type of cancer. Finally, we did not have serial samples drawn at sufficiently frequent intervals to determine the operative stage for the biomarker (e.g., whether adducts are early or late events or a combination). For example, we cannot necessarily assume that biomarkers 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. However, there is substantial evidence that adduct measures can serve as general indices of individual ecogenetic response to environmental carcinogens and can distinguish constitutionally "high responders" from "low responders" (12 , 25 , 35 , 40 , 42) . These high responders may have increased activation via P450 enzymes, decreased detoxification via the glutathione S-transferase pathway, and/or decreased DNA repair that are shared by lymphocytes and lung. In theory, current smokers who subsequently become cases would experience high levels of DNA damage, and smoking may induce the opposite effect in individuals who remain free of cancer. Thus, it is plausible that, in this relatively small number of subjects, the case-control difference was clearly evident only in the presence of ongoing challenge via active smoking. This may explain why the current smokers among the controls have lower levels than current smoker cases and why current smoker controls had lower adduct levels than former smoker controls.
In the present study in which we have controlled for differences in the major carcinogenic exposure detected by the assay (i.e., PAH and other aromatics in tobacco smoke) among current smokers but not among former and never-smokers, elevated PAH-DNA and other aromatic/hydrophobic carcinogen-DNA adducts in WBCs were significant predictors of lung cancer risk.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a Grant from the National Cancer Institute, NIH, #5RO1 CA 53772, "Molecular Epidemiology of Lung Cancer: a Nested Case-Control Study." 
2 To whom requests for reprints should be addressed, at Department of Environmental Health Sciences, Joseph L. Mailman School of Public Health, Columbia University, 60 Haven Avenue, B-109, New York, New York, 10032. Phone: (212) 304-7280; Fax: (212) 544-1943.
3 The abbreviations used are: PHS, Physicians’ Health Study; PAH, polycyclic aromatic hydrocarbon; BaP, benzo(a)pyrene; DRZ, diagonal radiation zone; SCLC, small cell lung carcinoma; NSCLC, non-SCLC; CPD, cigarettes smoked/day; OR, odds ratio; CI, confidence interval.
4 M. Stampfer, personal communication.
Received 5/ 1/01. Accepted 7/26/01.
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R. L. Divi, F. A. Beland, P. P. Fu, L. S. Von Tungeln, B. Schoket, J. E. Camara, M. Ghei, N. Rothman, R. Sinha, and M. C. Poirier Highly sensitive chemiluminescence immunoassay for benzo[a]pyrene-DNA adducts: validation by comparison with other methods, and use in human biomonitoring Carcinogenesis, December 1, 2002; 23(12): 2043 - 2049. [Abstract] [Full Text] [PDF]
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R. Godschalk, J. Nair, F.J. van Schooten, A. Risch, P. Drings, K. Kayser, H. Dienemann, and H. Bartsch Comparison of multiple DNA adduct types in tumor adjacent human lung tissue: effect of cigarette smoking Carcinogenesis, December 1, 2002; 23(12): 2081 - 2086. [Abstract] [Full Text] [PDF]
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 P. G. Shields Tobacco Smoking, Harm Reduction, and Biomarkers J Natl Cancer Inst, October 2, 2002; 94(19): 1435 - 1444. [Abstract] [Full Text] [PDF]
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 K Husgafvel-Pursiainen Molecular biomarkers in studies on environmental cancer J Epidemiol Community Health, October 1, 2002; 56(10): 730 - 731. [Full Text] [PDF]
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F. Perera, K. Hemminki, W. Jedrychowski, R. Whyatt, U. Campbell, Y. Hsu, R. Santella, R. Albertini, and J. P. O'Neill In Utero DNA Damage from Environmental Pollution Is Associated with Somatic Gene Mutation in Newborns Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1134 - 1137. [Abstract] [Full Text] [PDF]
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F. P. Perera, L. A. Mooney, M. Stampfer, D. H. Phillips, D. A. Bell, A. Rundle, S. Cho, W.-Y. Tsai, J. Ma, A. Blackwood, et al. Associations between carcinogen-DNA damage, glutathione S-transferase genotypes, and risk of lung cancer in the prospective Physicians' Health Cohort Study Carcinogenesis, October 1, 2002; 23(10): 1641 - 1646. [Abstract] [Full Text] [PDF]
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A. Besaratinia, L.M. Maas, E.M.C. Brouwer, E.J.C. Moonen, T.M.C.M. De Kok, G.J. Wesseling, S. Loft, J.C.S. Kleinjans, and F.J. Van Schooten A molecular dosimetry approach to assess human exposure to environmental tobacco smoke in pubs Carcinogenesis, July 1, 2002; 23(7): 1171 - 1176. [Abstract] [Full Text] [PDF]
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L. Airoldi, F. Orsi, C. Magagnotti, R. Coda, D. Randone, G. Casetta, M. Peluso, A. Hautefeuille, C. Malaveille, and P. Vineis Determinants of 4-aminobiphenyl-DNA adducts in bladder cancer biopsies Carcinogenesis, May 1, 2002; 23(5): 861 - 866. [Abstract] [Full Text] [PDF]
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