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O Ariginal rticle Smoking and the Risk of Lung Cancer Susceptibility with GSTP1 Polymorphisms David P. Miller,* Donna Neuberg/ Immaculata De Vivo, * John C. Wain, Thomas J. Lynch,11 Li Su, and David C. Christiani* Background: GSTP1 is a gene that helps detoxify foreign sub stances in the body. Functional polymorphisms of GSTP1 have been studied as risk factors for lung cancer. Past studies have compared the effect of the "at risk" polymorphism in two strata of smoking pack-years (usually defined by the median among controls). We examined the interaction between GSTP1 polymorphisms and cu mulative exposure to smoking and their association with lung cancer risk. Methods: Data are from a large hospital-based case-control study of persons treated for primary lung cancer at the Massachusetts General Hospital since 1992. Controls were drawn from friends and nonrelated family members. We genotyped 1,042 cases and 1,161 controls for GSTP1 using polymerase chain reaction-restriction fragment length polymorphism techniques. Findings: The GSTP1 GG genotype approximately doubled the lung cancer risk associated with pack-years. This interaction was stronger among current smokers. At 26 pack-years (median among controls with a smoking history), the adjusted odds ratio for the association between pack-years and lung cancer risk was 13 (95% confidence interval = 6.5-25) among current smokers with the GSTP1 GG genotype compared with 6.1 (95% confidence interval = 4.9-7.5) among those with the GSTP1 AA genotype Conclusions: GSTP1 GG increases the lung cancer risk associated with pack-years of smoking. Submitted 20 March 2002; final version accepted 18 March 2003. From the *Department of Environmental Heath, Occupational Health Pro gram, Harvard School of Public Health; fDepartment of Biostatistics, Harvard School of Public Health, Dana-Farber Cancer Institute; {De partment of Epidemiology, Harvard School of Public Health and Channing Laboratories, Harvard Medical School; Thoracic Surgery Unit, Department of Surgery, Department of Medicine, Massachusetts General Hospital, Harvard Medical School; ^Hematology Oncology Unit and ^Pulmonary and Critical Care Unit, Department of Medicine, Massachu setts General Hospital, Harvard Medical School, Boston, MA. Supported by National Institutes of Health Grants CA 74386, ES/CA 06409, and ES00002. Correspondence: David C. Christiani, Occupational Health Program, Harvard School of Public Health, 665 Huntington Avenue Bldg 1 Room 1402, Boston, MA 02115. E-mail: dchris@hohp.harvard.edu. Copyright 2003 by Lippincott Williams & Wilkins 1044-3983/03/1405-0545 DOI: 10.1097/01.ede.0000073120.46981.24 Epidemiology Volume 14, Number 5, September 2003 Key Words: GSTP1, lung cancer, case-control, susceptibility (Epidemiology 2003;14: 545-551) igarette smoke contains many carcinogens, including Cpolyaromatic hydrocarbons, n-nitrosamines, and aro matic amines.1 When inhaled, they enter the lung and then the bloodstream, where they are metabolized (generally) in a two-phase process.2 Phase I involves the "activation" of the carcinogen by oxygenation. This is mainly performed through cytochrome P450 enzymes encoded by the CYP gene superfamily. Phase II is the detoxification step, in which the "activated" carcinogen is rendered more hydrophilic, thus excretable. Glutathione S-transferases, a major group of en zymes whose main classes are a, p, t, and 6, are directly involved in the detoxification step of metabolism (phase II).2 The expression of these enzymes differs among organs. GST t has the highest expression in the lung and is one of the main detoxifiers of the activated form of benzopyrene (BPDE; 7,8-diole-9,10-epoxide), a major carcinogen of to bacco smoke.1,3,4 GST t is encoded by a polymorphic gene, GSTP1. One polymorphism of GSTP1 is caused by a single base pair substitution, where (A) adenine is replaced by (G) guanine, leading to an amino acid substitution in which isoleucine (I105) is replaced by valine (V105). This substitu tion results in a lower GST t enzymatic activity5,6 and is associated with higher hydrophobic adduct levels in lung tissue7 and higher levels of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human lymphocytes.8 GSTP1 polymorphisms may modify the association between a cumulative exposure to active smoking and lung cancer. Lung cancer risk is directly associated with increases in cumulative smoking exposure.9,10 Adduct levels have also been shown to increase in a dose-dependent manner in smokers.11 Lung cancer risk is also affected by other com ponents of a smoking history. Specifically, lung cancer risk increases with smoking status (nonsmoker, ex-smoker, cur rent smoker), and decreases with increasing number of years since smoking cessation.9 Previous studies have examined the 545 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited Miller et al Epidemiology Volume 14, Number 5, September 2003 modification of the association between smoking and lung cancer risk by polymorphisms in metabolism genes. Most studies have simply stratified lifetime exposure to cigarette smoking without considering possible effects of smoking status or years since smoking cessation.12-16 Few studies have examined the effect of polymorphisms on the association between a continuous cumulative smoking exposure and lung cancer risk also without considering smoking status.17,18 Yet, there is evidence that the time since a participant quit smok ing may affect the association between cumulative exposure to smoking and lung cancer. We investigated whether the GSTP1 GG genotype modified the association between a cumulative exposure to smoking and lung cancer risk, assuming that this association also differed by smoking status. We also examined the assumptions and resulting interpretation of common model ing approaches. METHODS We recruited subjects for this study as part of an ongoing hospital-based case- control study initiated in 1992 at the Massachusetts General Hospital (MGH), in Boston, MA. The study was approved by the Institutional Review Board at both Massachusetts General Hospital and Harvard School of Public Health. Eligible cases included any person over the age of 18 years with a diagnosis of primary lung cancer, evaluated by the pulmonary, thoracic surgery, or hematology- oncology units at MGH for either surgery (from 1992), chemotherapy (from 1996), radiation treatment, or any combination. An MGH lung pathologist histologically con firmed all cases. We recruited controls first among friends and non blood-related family members of the cases (usually spouses). If friends of lung cancer patients were not available, we recruited controls from friends and family of patients receiv ing thoracic surgery, chemotherapy, or radiation treatment of a condition other than lung cancer. To determine whether our controls were similar to the Massachusetts general popula tion, we compared important covariate data obtained from our controls with information provided by the Massachusetts Tobacco Survey, 1993 to 19979 and noted that the results were similar. Although the data were not restricted to resi dents of Massachusetts, 84% of the cases and 79% of the controls resided in Massachusetts, whereas 10% of the cases and 11% of the controls were from the rest of the New England area, respectively. The remainder of five cases (6%) and controls (10%) were from other regions of the United States. A research nurse sought and obtained informed consent from all cases and controls and proceeded to administer the health and diet questionnaires. Some participants opted to complete the questionnaires at home and returned them by mail in a self-addressed stamped envelope. Participants were contacted by telephone when there were missing data. The participation rate was over 85% and did not differ between cases and controls. To reduce potential variation in allele frequency by ethnicity, only whites were considered in the analysis. We collected blood samples from all participants at the time of recruitment. Two or three 10-ml EDTA tubes were used for sample collection. Samples were processed in the molecular epidemiology laboratory at the Harvard School of Public Health. DNA was extracted from whole blood for the purpose of genotyping. All genotyping was performed using polymerase chain reaction-restriction fragment length poly morphism techniques and blinded to case or control status. GSTP1 genotypes were determined using methods described by Harris et al.19 For quality control, a random 5% of the samples were repeated an found to be 100% concordant. Two authors independently reviewed all of the agarose gels and genotype data entry. Data on other variables were obtained through the health questionnaire.17,20,21 These included age, sex, race, weight, education, medical history, smoking history, family history of cancer, work history, exposure to various sub stances, participation in specific activities, and food prepara tion and consumption. We estimated cumulative exposure to cigarette smoking in pack-years by multiplying the mean number of packs smoked per day by the number of years of smoking, taking into account periods of smoking cessation. Smoking status is defined as current smoker (quit smoking less than a year from recruitment or current smoker), ex smoker (quit smoking more than a year before recruitment), and nonsmokers (smoked 100 cigarettes or less in a lifetime). Genotype frequencies were calculated among controls to test for Hardy-Weinberg equilibrium. We considered GSTP1 GG and AG genotypes separately in each model, thus avoiding the assumptions required to pool heterozygote and homozygote variants. The continuous variables used in the models were assessed to determine if any transformations were necessary. The square root transformation of the vari able for pack-years was used in the analyses. To assess whether GSPT1 GG modified the association between pack-years and lung cancer risk, we used a model with two interaction terms, one between genotype and packyears in current smokers and the another interaction between genotype and pack-years in ex-smokers (model A). Model A included indicator variables for the GSTP1 polymorphism (AG, GG), a continuous variable for pack-years among ex smokers (where the variable equals 0 if the participant is either a nonsmoker or a current smoker), and a continuous variable for pack-years among current smokers (where the variable equals 0 for nonsmokers and ex-smokers), and two separate interaction terms between GSTP1 GG and packyears for ex-smokers, and GSTP1 GG and pack-years for current smokers. 546 2003 Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited Epidemiology Volume 14, Number 5, September 2003 Smoking, Lung Cancer, and GSTP! Polymorphisms We also examined a model that assumes nonsmokers do not contribute to the estimate of lung cancer risk associ ated with pack-years (model B), and a model that assumes smoking status does not have an impact on the association between a cumulative smoking exposure and lung cancer risk (Model C). Model B considered a three-way interaction among genotype, smoking status and pack-years. Specifi cally, Model B contained indicator variables for the GSTP1 polymorphisms (AG, GG), smoking status (ex-smoker, cur rent smoker), pack-years, and all the two-way and three-way interactions of these variables. Model C considered an inter action term between genotype and pack-years only. Specifi cally, model C included indicator variables for the GSTP1 polymorphisms (AG, GG), smoking status (ex-smoker, cur rent smoker), pack-years, and an interaction term between GSTP1 GG and pack-years. All models included age, sex, and the number of years since a participant quit smoking (which was coded as zero for current and nonsmokers). We used the likelihood ratio test to evaluate the interaction terms.22 RESULTS Table 1 shows the basic characteristics of cases and controls. Cases were older and more likely to be men. As expected, there were a higher number of nonsmokers among controls compared with cases (36% vs. 6%). The median pack-years among smokers were significantly higher for cases (53 vs. 26) and the median number of years since an ex-smoker quit smoking was higher among controls (18 vs. 11). Although the frequency of participants without a college degree was similar for cases and controls (70% vs. 69%), there were fewer college graduates among cases (22% vs. 30%), with 8% of the data missing for cases, and 1% missing for controls. The overall genotype distribution did not differ sub stantially between cases and controls (Table 1). The genotype frequencies were in Hardy-Weinberg equilibrium among the controls. Adenocarcinoma cell type accounted for 39% of cases, squamous cell-type comprised 22%, and all others represented 20%. Cell type data were not available at the time the study was conducted for 195 cases (19%). Staging infor mation was available for 71% of the cases: stage I and II, 36%; stage III and IV, 35%. The relatively high percentage of early stage (potentially curable) cancers reflected a referral bias for this specialty hospital. Table 2 shows the distribution of the covariates from Table 1, stratified by polymorphisms. The distribution of polymorphisms was similar by sex and education. The fre quency of the GSTP1 GG genotype was highest among cases with squamous cell histology (15%). Among cases, the fre quencies of the GSTP1 AA and GG genotypes were higher among those who had ever smoked, whereas the frequency of the GSTP1 AG genotype was higher among nonsmokers. TABLE 1. Covariate Summary Data for Cases and Controls Cases (N = 1,042) Controls (N = 1,161) Age; median (range) Sex; no. (%) Male Female Education; no. (%) College degree No college degree Data not available Smoking status; no. (%) Nonsmokers Exsmokers Current smokers Pack-years; median (range)* Years quit smoking; median (range)T GST P1; no. (%) AA (wild-type) AG (heterozygote) GG (homozygote variant) Cell type; no. (%) Adenocarcinoma Squamous cell Other Data not available Stage; no. (%) I and II II and IV Data not available *Restricted to smokers. ^Restricted to ex-smokers. 66 (30-91) 60 (27-96) 555 (53) 487 (47) 534 (46) 627 (54) 231 (22) 728 (70) 83 (8) 349 (30) 795 (69) 17(1) 66 (6) 413 (36) 561 (54) 529 (45) 415 (40) 219 (19) 53 (0.15-231) 26 (0.03-210) 11 (1-59) 18 (1-65) 473 (46) 441 (42) 128 (12) 515 (44) 525 (45) 121 (11) 406 (39) 231 (22) 210 (20) 195 (19) 374 (36) 363 (35) 305 (29) Among controls, this pattern was reversed for the GSTP1 GG genotype: nonsmokers had the highest and the current smok ers had the lowest frequency. Stratification by genotype showed no important differences in the medians of packyears and number of years a participant quit smoking among cases and controls. The following crude odds ratios were calculated (using data from Table 2), to examine the risk of lung cancer associated with GSTP1 GG compared with AA genotype in the various smoking status strata: nonsmokers (OR = 0.86; 95% confidence interval [CI] = 0.32-2.24), ex-smokers (1.19; 0.78-1.82), and current smokers (1.95; 1.03-2.95). Table 3 shows the results of our gene-pack-years inter action analysis evaluating whether the association between pack-years and lung cancer risk is modified by the GSTP1 2003 Lippincott Williams & Wilkins 547 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited Miller et al Epidemiology Volume 14, Number 5, September 2003 TABLE 2. Covariate Summary Data for Cases and Controls by Genotype Genotype Cases (N = 1,042) GG AG AA Age; median (range) Sex (%) Male Female Education (%) College degree No college degree Data not available Smoking status (%) Nonsmokers Exsmokers Current smokers Pack-years*; median (range) Years quit smoking1) median (range) Cell type (%) Adenocarcinoma Squamous cell Other Data not available Stage (%) I and II II and IV Data not available *Restricted to smokers. ^Restricted to ex-smokers. 65 (36-84) 66 (30-90) 67 (31-91) 14 42 44 11 42 47 13 42 45 12 42 46 10 49 41 11 12 13 52 (1-136) 10 (1-41) 50 42 42 54 (1-204) 10 (1-53) 39 46 45 53 (1-231) 12 (1-59) 10 40 50 15 39 46 13 45 40 12 47 41 14 39 47 12 41 47 11 46 43 Controls (N = 1,161) GG AG AA 63 (29-84) 60 (27-96) 59 (27-84) 10 45 45 11 46 43 10 46 44 10 45 45 12 47 41 13 10 6 21 (1 -94) 23 (1-56) 45 45 47 30 (1-152) 18 (1-65) 42 45 47 25 (1-210) 17 (1-52) polymorphism. We selected a 26 pack-year increase to rep resent the adjusted odds ratios (AORs) because this was the median among controls, although the results are robust at other cutpoints. The table shows the adjusted odds ratios for the association between a 26 pack-year increase and lung cancer risk. Model A allows participants with zero pack-years (non smokers) to contribute to the estimate of dose-response by assuming that smokers and nonsmokers all have a baselinerisk of lung cancer in the absence of any exposure. More importantly, individuals with pack-years equal to zero (non smokers) actually contributed to the estimate for pack-years. The presence of the interaction terms was statistically signif icant (P < 0.01). The association between pack-years and lung cancer risk for ex-smokers and current smokers is substantially modified by the presence of the GSTP1 GG genotype (Table 3). The AOR for a 26 pack-year increase for ex-smokers with the GSTP1 AA genotype is 4.7 (CI = 3.9-5.8), and for ex-smokers with the GSTP1 GG genotype is 7.5 (4.2-14). The AOR for a 26 pack-year increase for current smokers with the GSTP1 AA genotype is 6.1 (4.97.5), and for the current smokers with the GSTP1 GG geno type is 13 (6.5-25). Figure 1 shows the lung cancer risk associated with increases in pack-years and stratified by smoking and genotype status (derived from Model A). Model B considered a three-way interaction among smoking status, pack-years, and genotype. This model as sumed that lung cancer risk differs not only by genotype but also by smoking status. Model B did not include nonsmokers in the calculation of the estimate for pack-years and assumed differences in risks at pack-years zero for current and ex smokers. As expected, all the calculated odds ratio estimates among the different strata of smoking status and genotypes evaluating the association between pack-years and lung can cer risk were reduced but still substantial. Model C evaluated an interaction between GSTP1 GG and pack-years only, assuming that lung cancer risk associ ated with pack-years is modified by genotype but not smok ing status. Participants with pack-years equal to zero (non smokers) contributed to this estimate. There was modest 548 2003 Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited Epidemiology Volume 14, Number 5, September 2003 Smoking, Lung Cancer, and GSTP1 Polymorphisms TABLE 3. Lung Cancer Risk Associated with an Increase in 26 Pack-years Stratified by Smoking Status and Genotype Model Genotype Odds Ratio 95% CI P Value for Interaction Model A* Ex-smokers Ex-smokers Current smokers Current smokers Model B* Ex-smokers Ex-smokers Current smokers Current smokers Model C* *See text for details. GSTP1 AA GSTP1 GG GSTP1 AA GSTP1 GG GSTP1 AA GSTP1 GG GSTP1 AA GSTP1 GG GSTP1 AA GSTP1 GG 4.7 3.9-5.8 P < 0.01 7.5 4.2-14 6.1 4.9-7.5 13 6.5-25 3.2 2.3-4.5 P = 0.64 3.4 1.4-8.3 5.8 3.5-9.9 6.6 1.3-34 3.7 2.8-5.0 P = 0.05 6.4 3.5-12 interaction by genotype (Table 3). Lung cancer risk associ ated with a 26 pack-year increase was 6.4 (CI = 3.5-11.7) with the GSTP1 GG compared with 3.7 (2.8-5.0) for GSTP1 FIGURE 1. Lung cancer risk associated with increases in packyears stratified by genotype and smoking status based on results from model A. Current GG, current smoker with GSTP1 GG genotype; Ex GG, ex-smoker with GSTP1 GG genotype; Current AA, current smoker with GSTP1 AA genotype; Ex AA, ex-smoker with GSTP1 AA genotype. AA. All three models (A, B, and C) evaluated the entire case- control population. DISCUSSION Modification of tobacco carcinogen metabolism is the basis of almost all xenobiotic metabolizing polymorphism stud ies of lung cancer risk. Thus, polymorphisms should be evalu ated as an effect modifier of the smoking-lung cancer risk association, through evaluation of gene-smoking interactions. Most studies have treated smoking as a confounder of the polymorphism-lung cancer risk association by adjusting for smoking variables in a logistic regression.7,12,13,15,23-25 In the specific case of the GSTP1 polymorphism, there are biologic data to suggest an association between the polymorphisms and intermediary markers of lung carcino genesis. GST t is involved primarily in the detoxification of BPDE,1,3,4 one of the main carcinogens in tobacco smoke. Ryberg and colleagues7 found substantially higher levels of DNA adducts in patients with the GSTP1 GG polymorphism compared with GSTP1 AA patients. Watson et al6 reported that the enzymatic activity on substrates (including BPDE) associated with the GSTP1 GG genotype was lower than the activity associated with GSTP1 AA genotype. Lung cancer risk is associated with several aspects of smoking exposure (cumulative smoking exposure, smoking status, number of years quit smoking).9 All these factors and their possible modification by metabolism genes should be considered when assessing smoking related lung cancer risk. If the exposure variable is collapsed into too few categories, the dose effect from a cumulative exposure and the way in 2003 Lippincott Williams & Wilkins 549 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited Miller et al Epidemiology Volume 14, Number 5, September 2003 which this can vary depending on an individual's genetic susceptibility profile can be missed Other studies have examined effect modification by genetic polymorphisms of the association between pack-years and lung cancer risk. These studies were mostly conducted by stratified analyses in which the risk associated with one gene is compared in two groups dichotomized by a preset amount of pack-years. London et al13 reported an AOR of 1.77 for GSTM1 Null and lung cancer risk among light smokers (<40 pack-years) but not in heavy smokers (AOR = 0.90). They used a cutoff point for smoking that was based on two previous studies. To-Figueras et al14 also reported an AOR of 1.77 for the association between GSTM1 Null and lung cancer risk among those with pack-years less than or equal to 50. The cutoff point was based on the median pack-years among cases because pack-year information for controls was not available. Kihara et al15 reported an increase in squamous cell lung cancer risk associated with the GSTM1 Null genotype when comparing the lowest category for cumulative smoke exposure (AOR = 0.8) to the highest (AOR = 3.1). Although Jourenkova-Mironova et al12 considered interactions of GSTP1, GSTM1, and GSTM3 with pack-years, they reported only the results of stratified analyzes. Lung cancer risk associated with the three deficient genotypes was higher among heavy smokers (<35 pack-years) compared with light smokers (>35 pack-years). The cutoff point was based on the distribution of pack-years among controls. In contrast, two studies investigated these gene-pack-year interactions, but considered a continuous variable for pack-years. We previ ously evaluated GSTM1 and CYP1A1 MSP1 genotypes as individual effect modifiers of the pack-years lung cancer risk association,17 and Nyberg et al18 separately examined similar associations with GSTM1 and NAT2 polymorphisms. No interaction was detected. However, both studies had small sample sizes, with lower power to detect interactions. Our study reports an interaction between GSTP1 GG and cumulative smoking exposure, measured in pack-years. Specifically, the GSTP1 GG genotype is associated with a substantially higher risk of lung cancer at any given level of exposure defined by pack-years, and the risk ratio for a 26 pack-year increase is greater for current smokers (GSTP1 GG AOR: 12.8; for GSTP1 AA, AOR = 6.1) compared with ex-smokers (GSTP1 GG, AOR = 7.5; for GSTP1 AA, AOR = 4.7) (model A). Even if we assume that the associ ation between pack-years and lung cancer risk is not modified by smoking status (model C), there is still interaction between genotype and lung cancer risk (for 26 pack-year increase: GSTP1 GG, AOR = 6.4; for GSTP1 AA, AOR = 3.7). An analysis removing outliers did not change the results. To assess fully the association between a continuous variable and outcome, a broad range of exposure is necessary. In the case of smoking and lung cancer, excluding nonsmok ers reduces this range and may alter what may be the true association between pack-years and lung cancer risk. In addition, power would be reduced by excluding nonsmokers from the study population (22%). Both models A and C allow for the nonsmokers (pack-years = 0) to contribute to the estimate of the coefficient for pack-years. In addition, model A accounts for differences in the gene-pack-years interaction because of smoking status, which is a biologically plausible assumption, whereas model B adjusts for smoking status as a confounder but assumes that the gene-pack-years interaction does not differ based on smoking status. Models with three-way interactions (model B) are a common approach when examining effect modification of the association between pack-years and lung cancer by two variables (smoking status and genotype). In this model, non smokers did not contribute to the estimate of the pack-years coefficient. However, excluding those at pack-years 0 from the estimate of the association between pack-years and lung cancer risk may not be biologically appropriate. This not only alters the association between smoking and lung cancer risk, but also affects the differences in this association in the different genotypic strata. Our study had several limitations. Recall bias can be a concern for our smoking exposure variables, which were collected through an administered health questionnaire. In choosing controls who are either friends or nonblood-related family member of cases, the motivation drive to recall expo sures possibly associated with lung cancer risk is more likely to be similar for cases and controls.26 However, our choice of controls leads to another concern: overmatching. The data show a wide distribution of our cumulative smoking expo sure. If the analysis results in an underestimation of the lung cancer risk associated with a cumulative smoking exposure, this should not affect the gene- environment analysis. A third limitation is that we did not have the power to stratify the data further by lung cancer cell type. In conclusion, the lung cancer risk associated with pack-years is substantially greater with the GSTP1 GG ge notype. This risk is greater for current smokers than for ex-smokers. Understanding the assumptions that underlie statistical models is critical to appropriate interpretations of these models. When assessing which model assumptions are appropriate, biologic plausibility should be considered.26 ACKNOWLEDGMENTS We gratefully acknowledge the assistance of Linda Lineback, Barbara Bean, Jeanne Jackson, and Andrea So lomon for patient recruitment and data collection; Lucy Ann Principe, Salvatore V. Mucci, and Richard Rivera-Massa for data entry; Stephanie Shih for sample preparation and genotyping; and Geoffrey Liu and Shannon Magari for editing advice and comments. 550 2003 Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited Epidemiology Volume 14, Number 5, September 2003 Smoking, Lung Cancer, and GSTP! Polymorphisms REFERENCES 1. Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999;91:1194-1210. (in process citation) 2. 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