David P. Miller

Second hand smoke, age of exposure and lung cancer risk

BACKGROUND Exposure to second hand smoke (SHS) has been identified as a risk factor for lung cancer for three decades. It is also known that the lung continues to grow from birth to adulthood, when lung growth stops. We hypothesize that after adjusting for active cigarette smoking, if SHS exposure took place during the period of growth, i.e. in the earlier part of life (0-25 years of age) the risk of lung cancer is greater compared to an exposure occurring after age 25. METHOD Second hand smoke exposure was self-reported for three different activities (leisure, work and at home) for this study population of 1669 cases and 1263 controls. We created variables that captured location of exposure and timing of first exposure with respect to a study participants age (0-25, >25 years of age). Multiple logistic regressions were used to study the association between SHS exposure and lung cancer, adjusting for age, gender and active smoking variables. RESULT For study participants that were exposed to SHS at both activities (work and leisure) and compared to one or no activity, the adjusted odds ratio (AOR) for lung cancer was 1.30 (1.08-1.57) when exposure occurred between birth and age 25 and 0.66 (0.21-1.57) if exposure occurred after age 25 years. Respective results for non-smokers were 1.29 (0.82-2.02) and 0.87 (0.22-3.38), and current and ex-smokers combined 1.28 (1.04-1.58) and 0.66 (0.15-2.85). CONCLUSION All individuals exposed to SHS have a higher risk of lung cancer. Furthermore, this study suggests that subjects first exposed before age 25 have a higher lung cancer risk compared to those for whom first exposure occurred after age 25 years.

Association between self-reported environmental tobacco smoke exposure and lung cancer: Modification by GSTP1 polymorphism

Environmental Tobacco Smoke (ETS) exposure has been associated with lung cancer risk. ETS is composed of emissions from cigarette smoke and contains a higher concentration of tobacco smoke carcinogens than mainstream smoke. Polymorphisms in genes that metabolize tobacco smoke carcinogens have been studied as effect modifiers of the association between active smoking and lung cancer risk. GSTP1 is a polymorphic gene that encodes for GST π, a detoxification enzyme and has a high expression in the lung. We investigated the association between ETS and lung cancer risk and the modification of this association by the GSTP1 polymorphism. Using a case‐control design, individuals were genotyped for GSTP1 using PCR‐RFLP techniques. All analyses were carried out using multiple logistic regression. The association between ETS exposure and lung cancer risk was evaluated in different strata based on smoking habits to evaluate the consistency of results. The effect of the GSTP1 polymorphisms on lung cancer risk was evaluated by considering the joint effect of having both an ETS exposure and the GSTP1 GG genotype compared to the absence of ETS exposure and the GSTP1 AA genotype as a reference group as well as doing stratified analysis by genotype. ETS exposure was associated consistently with higher lung cancer risk in all the strata considered. The adjusted odds ratios (AOR) evaluating the association between ETS and lung cancer risk for the different strata were: nonsmokers (Cases/Controls 66/413; AOR = 1.38; 95% CI = 0.78–2.43), ex‐smokers (Cases/Controls 560/527; AOR = 1.66; 95% CI = 1.22–2.25), current smokers (Cases/Controls 415/219; AOR = 1.56; 95% CI = 1.00–2.41). The AORs for ex‐smokers and light smoking subgroups were: ex‐smokers who quit for 19 years or more (Cases/Controls 144/244; AOR = 2.64; 95% CI = 1.55–4.50), ex‐smokers who quit for 10–19 years (Cases/Controls 141/128; AOR = 1.16; 95% CI = 0.66–2.04), ex‐smokers who quit for 10 years or less (Cases/Controls 247/122; AOR = 1.45; 95% CI = 0.83–2.55) and participants who had <15 packyears and nonsmokers combined (Cases/Controls 143/640; AOR = 1.52; 95% CI = 1.02–2.28). Among those with the GSTP1 GG genotype the ETS‐lung cancer risk association was greater than those with the GSTP1 AA genotype: nonsmokers (GSTP1 GG AOR = 7.84; 95% CI = 0.80–76.68; GSTP1 AA AOR = 1.15; 95% CI = 0.46–2.90), ex‐smokers (GSTP1 GG AOR = 2.32; 95% CI = 0.90–5.96; GSTP1 AA AOR = 2.15; 95% CI = 1.34–3.44),, current smokers (GSTP1 GG AOR = 1.75; 95% CI = 0.42–7.32; GSTP1 AA AOR = 1.32; 95% CI = 0.67–2.58) and participants who had <15 packyears and nonsmokers (GSTP1 GG AOR = 1.93; 95% CI = 0.54–6.97; GSTP1 AA AOR = 1.58; 95% CI = 0.83–3.01). We found that ETS exposure is associated with higher lung cancer risk. Furthermore, the presence of the GSTP1 GG genotype appears to enhance the magnitude of the association between ETS exposure and lung cancer. Larger studies will be needed to confirm these preliminary findings.

The SOD2 Val/Val genotype enhances the risk of nonsmall cell lung carcinoma by p53 and XRCC1 polymorphisms

Exogenous reactive oxygen species (ROS) induces DNA damage. Manganese superoxide dismutase (SOD2) catalyzes the dismutation of superoxide radicals, a major type of ROS, into hydrogen peroxide. p53 is a tumor suppressor gene, and X‐ray cross‐complementing group 1 (XRCC1) is involved in the base‐excision repair of ROS‐induced DNA damage.

Smoking and the risk of lung cancer: susceptibility with GSTP1 polymorphisms.

Background: GSTP1 is a gene that helps detoxify foreign substances 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 cumulative 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.

Dietary iron, zinc, and calcium and the risk of lung cancer.

Background: Iron, zinc, and calcium are all involved in the metabolism of reactive oxygen species and may compete with each other for similar binding sites. Dietary intakes of these micronutrients have been associated with altered risks of colorectal, breast, and prostate cancers. Methods: In this Massachusetts hospital-based case–control study of 923 patients with lung cancer and 1125 healthy controls, we studied the associations between dietary iron, zinc, and calcium intake and the risk of lung cancer. Dietary intake was assessed at the time of recruitment (1992 to 2000) with the use of a 126-item semiquantitative food-frequency questionnaire. We analyzed the data using multiple logistic regression models adjusting for smoking history and other potential risk factors. Results: The adjusted odds ratios of dietary iron, zinc, and calcium from food sources were 1.45 (95% confidence interval = 1.03–2.06), 0.71 (0.50–0.99), and 1.64 (1.17–2.29), respectively, for the highest quintile versus the lowest quintile of each micronutrient. Stronger associations between micronutrients and lung cancer risk were found when iron, zinc, and calcium were included together in the same model. The associations between dietary micronutrients intake and lung cancer risk were stronger among current smokers than among former smokers. When we examined intake from supplements as well as diet, associations were similar to those for diet alone. Conclusions: Dietary iron, zinc, and calcium may play an important role in the development of lung cancer, especially among current smokers. These results need to be confirmed in large prospective studies.

A case-control study of GST polymorphisms and arsenic related skin lesions

BackgroundPolymorphisms in GSTT1, GSTM1 and GSTP1 impact detoxification of carcinogens by GSTs and have been reported to increase susceptibility to environmentally related health outcomes. Individual factors in arsenic biotransformation may influence disease susceptibility. GST activity is involved in the metabolism of endogenous and exogenous compounds, including catalyzing the formation of arsenic-GSH conjugates.MethodsWe investigated whether polymorphisms in GSTT1, GSTP1 and GSTM1 were associated with risk of skin lesions and whether these polymorphisms modify the relationship between drinking water arsenic exposure and skin lesions in a case control study of 1200 subjects frequency matched on age and gender in community clinics in Pabna, Bangladesh in 2001–2002.Results and discussionGSTT1 homozygous wildtype status was associated with increased odds of skin lesions compared to the null status (OR1.56 95% CI 1.10–2.19). The GSTP1 GG polymorphism was associated with greater odds of skin lesions compared to GSTP1 AA, (OR 1.86 (95%CI 1.15–3.00). No evidence of effect modification by GSTT1, GSTM1 or GSTP1 polymorphisms on the association between arsenic exposure and skin lesions was detected.ConclusionGSTT1 wildtype and GSTP1 GG are associated with increased risk of skin lesions.

Modeling Lung Cancer Risk in Case-Control Studies Using a New Dose Metric of Smoking

Many approaches have been taken to adjust for smoking in modeling cancer risk. In case-control studies, these metrics are often used arbitrarily rather than being based on the properties of the metric in the context of the study. Depending on the underlying study design, hypotheses, and base population, different metrics may be deemed most appropriate. We present our approach to evaluating different smoking metrics. We examine the properties of a new metric, “logcig-years”, that we initially derived from using a biological model of DNA adduct formation. We compare this metric to three other smoking metrics, namely pack-years, square-root pack-years, and a model in which smoking duration and intensity are separate variables. Our comparisons use generalized additive models and logistic regression to examine the relationship between the logit probability of cancer and each of the metrics, adjusting for other covariates. All models were fit using data from a lung cancer study of 1,275 cases and 1,269 controls that has focused on gene-smoking relationships. There was a very significant, linear relationship between logcig-years and the logit probability of lung cancer in this sample, without any need to adjust for smoking status. These properties together were not shared by the other metrics. In this sample, logcig-years captured more information about smoking that is important in lung cancer risk than the other metrics. In conclusion, we provide a general framework for evaluating different smoking metrics in studies where smoking is a critical variable.

P53 (codon 72) and P21 (codon 31) polymorphisms alter in vivo mRNA expression of p21

p21 (Waf1/Cip1) is a downstream target of p53. We evaluated the association between p21 polymorphism (codon 31), p53 polymorphism (codon 72) and their corresponding in vivo mRNA expression. In this study, p21 and p53 genetic polymorphisms (using standard PCR-RFLP techniques) and p21 and p53 gene expressions (using a radiolabelled ribonuclease protection assay (RPA) technique) were evaluated in the peripheral leukocytes of 84 individuals (63 with lung cancer). Log-transformed values of mRNA expression by RPA, which approximated a normal distribution, were analyzed. p53 genotypes did not correlate with p53 mRNA log-expression (P>0.05 for all comparisons), but the Pro allele variants of p53 were associated with a significant decrease in mRNA log-expression of its downstream target, p21. The variant Arg allele of p21 was also associated with a significant decrease in p21 mRNA log-expression. When individuals with at least one variant allele of both p53 and p21 (double-variants) were compared with all other genotype groups, these double-variants had significantly lower log-expression of p21 (P<0.005 by both t-tests (crude) and linear regression analyses (adjusted)). This is translated into an approximate 48% reduction in the geometric mean of the mRNA expression of the double-variants, when compared with all other groups. Results were consistent in both patients with lung cancer (n=63) and in normal controls (n=21). In conclusion, the presence of a p53 Pro allele and/or p21 Arg allele is associated with lower downstream target gene expression of p21.

An association between glutathione S-transferase P1 gene polymorphism and younger age at onset of lung carcinoma

Among the genes that encode the glutathione S‐transferase (GST) superfamily of Phase 2 metabolizing enzymes, GSTP1 has the highest expression in the lung. The polymorphic GSTP1 gene encodes glutathione S‐transferase π, which is an enzyme that detoxifies cigarette carcinogens, such as benzo‐[a]‐pyrene. The variant GSTP1 GG genotype is associated with lower enzymatic activity and higher DNA adduct levels in human lymphocytes compared with the AA genotype.

Second Hand Smoke Exposure and Survival in Early-Stage Non–Small-Cell Lung Cancer Patients

Purpose: Second hand smoke (SHS) exposure is associated with higher risk of lung cancer. However, the role of SHS in lung cancer survival is not clear. Experimental Design: We examined the association between self-reported SHS exposure before diagnosis and overall survival and recurrence-free survival in 393 early-stage non–small-cell lung cancer patients. SHS exposure was analyzed by both duration and location of exposure using log-rank test and Cox proportional hazard models, adjusting for covariates including pack-years of smoking. Results: The median follow-up time was 66 months (range, 0.2-140 months). There were 135 recurrences and 213 deaths. The 5-year overall survival rates were 71% [95% confidence interval (95% CI), 62-81%], 61% (51-72%), 49% (38-60%), and 47% (37-58%), respectively, for patients with the lowest to highest quartile of SHS exposure durations (P < 0.001, log-rank test), with the adjusted hazard ratio (AHR) of 1.57 (95% CI, 1.02-2.41) for the highest versus lowest quartile of SHS exposure durations (Ptrend = 0.04). For different SHS exposure locations, a stronger association was found for SHS exposure at work (AHR of the highest versus lowest quartile, 1.71; 95% CI, 1.12-2.61; Ptrend = 0.03) than for exposure at home (AHR, 1.26; 95% CI, 0.86-1.86; Ptrend = 0.20) or leisure places (AHR, 1.28; 95% CI, 0.83-1.95; Ptrend = 0.16). Similar associations were observed when SHS exposure durations were dichotomized into two or three groups and between SHS exposure and recurrence-free survival. Conclusions: SHS exposure is associated with worse survival in early-stage non–small-cell lung cancer patients, especially for SHS exposure at the work.