Environment And Genetics In Lung Cancer Etiology Research Articles

Outdoor particulate matter (PM10) exposure and lung cancer risk in the EAGLE study

ObjectiveCohort studies in Europe, but not in North-America, showed an association between exposure to outdoor particulate matter with aerodynamic diameter ≤10 μm (PM10) and lung cancer risk. Only a case-control study on lung cancer and PM10 in South Korea has so far been performed. For the first time in Europe we analyzed quantitatively this association using a case-control study design in highly polluted areas in Italy.MethodsThe Environment And Genetics in Lung cancer Etiology (EAGLE) study, a population-based case-control study performed in the period 2002–2005 in the Lombardy Region, north-west Italy, enrolled 2099 cases and 2120 controls frequency-matched for area of residence, gender, and age. For this study we selected subjects with complete active and passive smoking history living in the same municipality since 1980 until study enrollment. Fine resolution annual PM10 estimates obtained by applying land use regression modeling to satellite data calibrated with fixed site monitor measurements were used. We assigned each subject the PM10 average estimates for year 2000 based on enrollment address. We used logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI) adjusted for matching variables, education, smoking, and dietary and occupational variables.ResultsWe included 3473 subjects, 1665 cases (1318 men, 347 women) and 1808 controls (1368 men, 440 women), with PM10 individual levels ranging from 2.3 to 53.8 μg/m3 (mean: 46.3). We found increasing lung cancer risk with increasing PM10 category (P-value for trend: 0.04). The OR per 10 μg/m3 was 1.28 (95% CI: 0.95–1.72). The association appeared stronger for squamous cell carcinoma (OR 1.44, 95% CI: 0.90–2.29).ConclusionIn a population living in highly polluted areas in Italy, our study added suggestive evidence of a positive association between PM10 exposure and lung cancer risk. This study emphasizes the need to strengthen policies to reduce airborne pollution.

Nut Consumption and Lung Cancer Risk: Results from Two Large Observational Studies.

Background: Epidemiologic evidence on the association between nut consumption and lung cancer risk is limited.Methods: We investigated this relationship in the Environment and Genetics in Lung Cancer Etiology (EAGLE) study, a population-based case-control study, and the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study, a prospective cohort. We identified 2,098 lung cases for EAGLE and 18,533 incident cases in AARP. Diet was assessed by food frequency questionnaire for both studies. Multivariable ORs and HRs and respective 95% confidence intervals (CI) were calculated using unconditional logistic regression and Cox proportional hazards regression for EAGLE and AARP, respectively.Results: Higher frequency of intake of nut consumption was inversely associated with overall lung cancer risk (highest vs. lowest quintile, OREAGLE = 0.74; 95% CI, 0.57-0.95; HRAARP = 0.86; 95% CI, 0.81-0.91), regardless of smoking status. Results from the prospective cohort showed similar associations across histologic subtypes and a more pronounced benefits from nut consumption for those who smoked 1 to 20 cigarettes/day (OREAGLE = 0.61; 95% CI, 0.39-0.95; HRAARP = 0.83; 95% CI, 0.74-0.94).Conclusions: Nut consumption was inversely associated with lung cancer in two large population-based studies, and associations were independent of cigarette smoking and other known risk factors.Impact: To our knowledge, this is the first study that examined the association between nut consumption and lung cancer risk by histologic subtypes and smoking intensity. Cancer Epidemiol Biomarkers Prev; 26(6); 826-36. ©2017 AACR.

Highlights of This Issue

Toth and colleagues used a subsets (ASSET) meta-analytic approach, to investigate associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas. Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. Variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, ER-negative breast, overall prostate, overall and serous ovarian cancer. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, overall and aggressive prostate cancer risk. Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology.Lee and colleagues investigated the relationship between nut consumption and lung cancer in the Environment And Genetics in Lung cancer Etiology (EAGLE) study and the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study. The study found higher frequency of intake of nut consumption was inversely associated with overall lung cancer risk and associations were independent of cigarette smoking and other known risk factors.Li-Fraumeni syndrome (LFS) is associated with germline TP53 mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are ofta model en used in clinical counseling. Existing LFS criteria have limitations. Peng and colleagues present a Mendelian model, LFSPRO, which estimates TP53 mutation probability through the Elston-Stewart algorithm, and consequently estimates future risk of cancer. LFSPRO accurately predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center. LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS.Men of African descent experience a disproportionately high prostate cancer mortality and studies have shown that prostate tumors in African-American (AA) patients harbor a distinct immune and inflammation signature when compared with European-American (EA) patients. Smith and colleagues examined the relationship between aspirin use and prostate cancer in the NCI-Maryland Prostate Cancer Case-Control Study consisting of men with incident prostate cancer and population-based men without the disease diagnosis. The authors report a significant inverse association between regular aspirin use and prostate cancer among AA men. Regular aspirin use before and after a prostate cancer diagnosis may prevent the development of aggressive disease in AA men who are at risk of a lethal malignancy.

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study.

BackgroundLung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.Methods and FindingsWe performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10−50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10−4) were associated with increased risk of distant metastasis. Our study’s limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality.ConclusionsThese data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD’s high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.

Abstract A34: Association of nut consumption and lung cancer risk in a large population-based case-control study

Abstract Background: Increased nut consumption has been associated with a reduced risk of major chronic diseases, including type 2 diabetes mellitus, gallstone disease, and colon cancer. However, the association between nut consumption and lung cancer risk is unclear. Methods: We investigated the association of nut consumption (walnuts, hazelnuts, almonds, or peanuts) with lung cancer risk in the Environment And Genetics in Lung cancer Etiology (EAGLE), a population-based case-control study. Primary lung cancer cases (n= 2101) were enrolled within the Lombardy region of Italy and matched (on gender, residence, and age) to randomly selected controls (n = 2120). Diet was assessed in 1903 cases and 2073 controls. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific quintiles of intake were calculated using unconditional logistic regression, adjusted for putative confounders including smoking. Results: Nut consumption was negatively associated with lung cancer risk (ORQ5-VS-Q1 = 0.72; 95% CI: 0.56-0.92; p-trend =0.014); the association did not change marginally after additional adjustment for consumption of fruits and vegetables (ORQ5-VS-Q1 = 0.74, 95% CI = 0.58-0.95, p-trend = 0.028). Conclusion: In summary, dietary nut consumption was associated with reduced risk of lung cancer in EAGLE. Citation Format: Tram Kim Lam, Dario Consonni, Angela Pesatori, Pier Alberto Bertazzi, Maria Teresa Landi. Association of nut consumption and lung cancer risk in a large population-based case-control study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A34.

Association of Nut Consumption and Lung Cancer Risk in a Large Population‐based Case‐control Study

Increased nut consumption has been associated with a reduced risk of colon cancer. No study has examined the association between nut consumption and lung cancer risk. We investigated the association of nut consumption (walnuts, hazelnuts, almonds, or peanuts) with lung cancer risk in the Environment And Genetics in Lung cancer Etiology (EAGLE), a population‐based case‐control study. Primary lung cancer cases (n=2101) were enrolled within the Lombardy region of Italy and matched (on gender, residence, and age) to randomly selected controls (n=2120). Diet was assessed in 1903 cases and 2073 controls. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for sex‐specific quintiles of intake were calculated using unconditional logistic regression, adjusted for putative confounders. Nut consumption was statistically associated with reduced risk of lung cancer (ORQ5‐vs‐Q1=0.73;95% CI:0.57‐0.94) and similar statistically significant associations were observed across histological subtypes. The protective association was strongest among ever smokers who smoked 蠄15 cigarettes per day (ORQ5‐vs‐Q1=0.59,95% CI=0.39‐0.90); no significant association, however, was observed for ever‐smokers who smoked &gt;15 cigarettes per day (ORQ5‐vs‐Q1=0.80,95% CI=0.58‐1.10). In summary, we observed an inverse association between nut consumption and lung cancer risk. Our findings suggest a stronger benefit for light smokers. Further research on this relationship is warranted in prospective cohort studies.

Abstract 2157: Causal effects of delaying smoking initiation on subsequent lung cancer risk

Abstract Background: Methods that report relative risks when describing the association between age at smoking initiation and lung cancer adjust for variables unknown or unpredictable at the time of initiation (smoking duration, pack-years etc.). Such methods do not provide valid estimates of the causal effect of smoking initiation. Also, relative risks are not informative for assessing the effects of youth smoking prevention programs or describing the impact of individuals' decisions to start smoking. Applying a causal modelling framework, we estimate absolute lung cancer risk - a metric more relevant to public health than relative risk - given variables fixed at the age of smoking initiation and averaging over subsequent smoking behaviors. Methods: We used the Environment And Genetics in Lung cancer Etiology (EAGLE) study (1942 lung cancer cases, 2116 controls), a population-based case-control study in Lombardy, Italy. We classified risk factors as fixed at smoking initiation (gender, childhood exposure to tobacco smoke [CETS], lung cancer family history [FH], birth cohort) and as causally related to the initiation age (pack-years, cigarettes per day, quitting, nicotine dependency). Using the sampling fractions for controls selection, we reconstructed the original study cohort and estimated absolute lung cancer risks overall and conditionally on fixed factors. We predicted lung cancer rates for different ages at smoking initiation as number of cases per 100,000 person-years (PY) using a binomial linear model and estimated corresponding risk differences (RD) and 95% confidence intervals (CI). Instead of adjusting for the effects of smoking behaviors that happen after initiation, we averaged over them. We show how assumptions about factors unknown at smoking initiation affect the estimates. Results: Delaying smoking initiation from age 16 to age 20 reduces estimated lung cancer rate in men from 149 to 78 cases per 100,000 PY with a RD=71 (95% CI 25 to 120), but there is apparently no corresponding effect in women (RD= -1 [95% CI -50 to 48] from 26 to 27 cases per 100,000 PY). The effect of delaying initiation is larger for those without CETS (RD=113 [95% CI 52 to 174] cases per 100,000 PY from 156 to 43) than those with CETS (RD=45 [95% CI -2 to 92] cases per 100,000 PY from 92 to 47). For those with FH RD was 214 (95% CI -106 to 534) cases per 100,000 PY from 282 to 68, and for those without FH it was 44 (95% CI 3 to 85) cases per 100,000 PY from 85 to 41). RDs were greater for early birth cohorts. There was heterogeneity among individuals with same initiation age but different subsequent smoking behaviors. Conclusion: We estimated absolute lung cancer risk from a case-control study using information fixed at the initiation age and averaging over subsequent smoking behaviors. Our estimates show substantial impact of delaying initiation in men, even if the person eventually smokes. Extrapolation to current youths and young adults requires integration of data on contemporary smoking patterns. Citation Format: Orestis A. Panagiotou, Fangyi Gu, Carolyn Reyes-Guzman, Maria-Teresa Landi, Michele Bloch, Neil E. Caporaso, Sholom Wacholder. Causal effects of delaying smoking initiation on subsequent lung cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2157. doi:10.1158/1538-7445.AM2014-2157

Abstract 4150: Nicotine dependence impacts the relationship between genetic variants and risk of lung adenocarcinoma

Abstract Lung cancer, the leading cause of cancer death, accounted for 27% of cancer deaths for Americans in 2013. Despite its negative impact on public health, effective early detection tools for lung cancer are still under development. Several genetic variations associated with lung cancer risk and smoking behavior have been identified in some genome-wide association studies. It is unclear, however, if the gene variants affect lung cancer risk directly or indirectly through nicotine dependence. In an attempt to elucidate the relationships between lung cancer, genetic variants and smoking, we applied mediation analysis to quantify the impact of nicotine dependence. We evaluated 37 single nucleotide polymorphisms (SNPs) in nine candidate genes (TERT, CLPTM1L, CHRNB3, CHRNA6, CHRNA5/A3/B4, CYP1A1, and TP53), previously reported to be associated with lung cancer risk or with smoking behavior. A total of 661 lung adenocarcinoma (ADC) cases and 1,347 controls with a smoking history obtained from the Environment and Genetics in Lung Cancer Etiology (EAGLE) case-control study were included in the study. Results show that nicotine dependence is a mediator of the association between lung ADC and gene variations of CHRNA3 and CHRNB4 and accounts for approximately 20% of this relationship. The association between two CHRNA3 SNPs (rs1051730 and rs12914385) and risk for lung ADC reached a genome-wide significance (p-value=1.9x10-10 and 1.1x10-10, respectively). Also, these two SNPs had the most significant indirect effect on lung ADC risk through nicotine dependence (p=7x10-5 and 3x10-4). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had a significant direct association on lung ADC without an indirect effect through nicotine dependence. In addition, rs6474414 in CHRNB3 and rs4646421 in CYP1A1, were associated with nicotine dependence but not directly with lung ADC risk. Our findings provide valuable information for understanding the pathogenesis and for developing potentially effective screening tools for lung ADC. These identified SNPs may improve prediction accuracy of lung ADC at earlier stages, which is essential to enhancing survival rates. Translating these findings into public health practice may lead to tailored and customized smoking cessation interventions for Individuals with genetic variants, which have both direct and indirect effect through nicotine dependence on lung ADC. Citation Format: Tung-Sung Tseng, Jong Y. Park, Jovanny Zabaleta, Sarah Moody-Thomas, Melinda S. Sothern, Ted Chen, Hui-Yi Lin. Nicotine dependence impacts the relationship between genetic variants and risk of lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4150. doi:10.1158/1538-7445.AM2014-4150

Combined analysis with copy number variation identifies risk loci in lung cancer.

Background. Lung cancer is the most important cause of cancer mortality worldwide, but the underlying mechanisms of this disease are not fully understood. Copy number variations (CNVs) are promising genetic variations to study because of their potential effects on cancer. Methodology/Principal Findings. Here we conducted a pilot study in which we systematically analyzed the association of CNVs in two lung cancer datasets: the Environment And Genetics in Lung cancer Etiology (EAGLE) and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial datasets. We used a preestablished association method to test the datasets separately and conducted a combined analysis to test the association accordance between the two datasets. Finally, we identified 167 risk SNP loci and 22 CNVs associated with lung cancer and linked them with recombination hotspots. Functional annotation and biological relevance analyses implied that some of our predicted risk loci were supported by other studies and might be potential candidate loci for lung cancer studies. Conclusions/Significance. Our results further emphasized the importance of copy number variations in cancer and might be a valuable complement to current genome-wide association studies on cancer.

Heme-related gene expression signatures of meat intakes in lung cancer tissues.

Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) ≤ 0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR = 0.12). Sixty-three (∼ 28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer.

Are Women Who Smoke at Higher Risk for Lung Cancer Than Men Who Smoke?

Worldwide lung cancer incidence is decreasing or leveling off among men, but rising among women. Sex differences in associations of tobacco carcinogens with lung cancer risk have been hypothesized, but the epidemiologic evidence is conflicting. We tested sex-smoking interaction in association with lung cancer risk within a population-based case-control study, the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study (Lombardy, Italy, 2002-2005). Detailed lifetime smoking histories were collected by personal interview in 2,100 cases with incident lung cancer and 2,120 controls. Odds ratios and 95% confidence intervals for pack-years of cigarette smoking were estimated by logistic regression, adjusted for age, residence area, and time since quitting smoking. To assess sex-smoking interaction, we compared the slopes of odds ratios for logarithm of pack-years in a model for men and women combined. Overall, the slope for pack-years was steeper in men (odds ratio for female-smoking interaction = 0.39, 95% confidence interval: 0.24, 0.62; P < 0.0001); after restriction to ever smokers, the difference in slopes was much smaller (odds ratio for interaction = 0.63, 95% confidence interval: 0.29, 1.37; P = 0.24). Similar results were found by histological type. Results were unchanged when additional confounders were evaluated (e.g., tobacco type, inhalation depth, Fagerström-assessed nicotine dependence). These findings do not support a higher female susceptibility to tobacco-related lung cancer.

Authors' response to: Qualitative job-exposure matrix--a tool for the quantification of population-attributable fractions for occupational lung carcinogens?

Authors' response to: Qualitative job-exposure matrix--a tool for the quantification of population-attributable fractions for occupational lung carcinogens?

A blood-based gene expression signature of early-stage non-small cell lung cancer.

69 Background: Accurate blood-based biomarker for early cancer detection could be an easier and more convenient screening option than monitoring the target organ via tissue or imaging. We recently identified and validated eight genetic biomarkers of early-stage lung adenocarcinoma detectable in both peripheral whole blood (PWB) and lung tissue of smokers. Since biomarkers distinguishing benign disease versus lung malignancy across all cell types are needed in the diagnostic clinical setting, it is important to test the identified biomarkers in other lung cancer histologies, particularly in squamous cell carcinoma (SQCC), the second most common lung cancer histology after adenocarcinoma (AD). Methods: Using Real-Time Quantitative PCR (qRT-PCR), we measured mRNA levels for the eight candidate genes in PWB of 48 randomly sampled stage I SQCC cases, in addition to previously analyzed 82 AD cases and 130 age, sex, and smoking frequency matched healthy controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study. The qRT-PCR data were analyzed using the 2-ΔΔCtmethod to compare SQCC cases with controls. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the candidate biomarkers in SQCC separately, and in SQCC and AD together. Results: Expression of TGFBR3, RUNX3, TRGC2, TRGV9, TARP, and TSTA3 genes, significantly differentiated SQCC cases versus controls, while ACP1 and VCAN gene expression did not. The eight genes combined discriminated patients with lung cancer from healthy controls with similarly high accuracy in SQCC and overall (AUC = 0.80 ± 0.1). RUNX3 showed the highest single gene accuracy for SQCC (AUC = 0.78). Conclusions: We showed that the previously identified gene expression signature of early-stage lung AD also differentiated early stage SQCC from healthy controls and demonstrated its sensitivity and specificity as a potential diagnostic lung cancer biomarker. Since lung cancer is the most common cause of cancer mortality worldwide and current smokers are at very high risk, our smoking-specific findings, if confirmed and translated into screening approaches, have the potential to impact public health.

Mood Disorders and Risk of Lung Cancer in the EAGLE Case-Control Study and in the U.S. Veterans Affairs Inpatient Cohort

BackgroundMood disorders may affect lung cancer risk. We evaluated this hypothesis in two large studies.Methodology/Principal FindingsWe examined 1,939 lung cancer cases and 2,102 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study conducted in Italy (2002–2005), and 82,945 inpatients with a lung cancer diagnosis and 3,586,299 person-years without a lung cancer diagnosis in the U.S. Veterans Affairs Inpatient Cohort (VA study), composed of veterans with a VA hospital admission (1969–1996). In EAGLE, we calculated odds ratios (ORs) and 95% confidence intervals (CI), with extensive adjustment for tobacco smoking and multiple lifestyle factors. In the VA study, we estimated lung cancer relative risks (RRs) and 95% CIs with time-dependent Poisson regression, adjusting for attained age, calendar year, hospital visits, time within the study, and related previous medical diagnoses. In EAGLE, we found decreased lung cancer risk in subjects with a personal history of mood disorders (OR: 0.59, 95% CI: 0.44–0.79, based on 121 lung cancer incident cases and 192 controls) and family history of mood disorders (OR: 0.62, 95% CI: 0.50–0.77, based on 223 lung cancer cases and 345 controls). The VA study analyses yielded similar results (RR: 0.74, 95% CI: 0.71–0.77, based on 2,304 incident lung cancer cases and 177,267 non-cancer person-years) in men with discharge diagnoses for mood disorders. History of mood disorders was associated with nicotine dependence, alcohol and substance use and psychometric scales of depressive and anxiety symptoms in controls for these studies.Conclusions/SignificanceThe consistent finding of a relationship between mood disorders and lung cancer risk across two large studies calls for further research into the complex interplay of risk factors associated with these two widespread and debilitating diseases. Although we adjusted for smoking effects in EAGLE, residual confounding of the results by smoking cannot be ruled out.

Abstract 2647: Influence of quercetin-rich foods intake on microRNA expression in EAGLE lung cancer tissues

Abstract Background: Lung cancer is one of the most common cancers worldwide and has the highest cancer-related mortality rate. Dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the Environment and Genetics in Lung Cancer Etiology (EAGLE) study, have reported increased consumption of quercetin-rich foods to be inversely associated with lung cancer incidence. Although experimental studies suggest that quercetin might affect microRNA (miRNA) expression, this mechanism has not been fully examined. We investigated this hypothesis in quercetin-related lung carcinogenesis using lung cancer tissues. Methods: miRNA expression data were derived from formalin-fixed paraffin-embedded tissue samples in 264 lung (144 adenocarcinoma and 120 squamous cell carcinoma) cases from EAGLE using a custom-made, two-channel oligo array. Quercetin-rich foods were derived from food frequency questionnaire. Individuals were categorized into high and low consumers based on sex-specific tertiles of quercetin-rich food intake. We compared the expression of miRNAs (n=198) between lung cancer cases consuming high-versus-low quercetin-rich food intake using multivariate ANOVA test. We identified miRNAs whose expression differentiated high and low consumption (p-value&amp;lt;0.05), and further grouped them based on their biological function using MiRBase release 17.0. miRNA families were analyzed using Functional Class Scoring (FCS). All analyses were conducted for adenocarcinoma and squamous cell carcinoma separately. Further analyses included stratification by smoking status (former and current smokers only). Results: We found that miRNA expression of 56 miRNAs significantly distinguished lung cancer cases who consumed high-versus-low quercetin-rich foods in tumor tissue within smoking-specific histological subtypes (p-value&amp;lt;0.05). FCS analyses of these miRNAs identified the let-7 family to strongly differentiate between high-versus-low quercetin-rich cases (p-value&amp;lt;0.001), followed by miR-146, miR-125, miR-26, and miR-17 (p-value&amp;lt;0.05). Conclusions: We observed differential expression of key biologically functional miRNAs between high-versus-low consumers of quercetin-rich foods. Our findings, the first of this kind, warrant confirmation from larger studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2647. doi:1538-7445.AM2012-2647

Abstract 630: Tobacco smoking women are not at higher risk than men for lung cancer

Abstract Background. Worldwide lung cancer incidence is decreasing or leveling off among men, but rising among women. Gender differences in the effect of tobacco carcinogens on lung cancer risk have been hypothesized, but the epidemiologic evidence is conflicting. Objective. To test gender-smoking interaction in the association with lung cancer risk within the large Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study, conducted in Italy between 2002-2005. The study collected detailed lifetime smoking histories by personal interview. Methods. Separately for males and females, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for cumulative exposure to smoking (pack-years) by logistic regression, adjusted for age, residence area, and time since quitting smoking. We evaluated several potential confounders and effect-modifiers, including tobacco type, inhalation depth, percentage of each cigarette smoked, and visualized the tobacco dose-response relationship across genders through floating trends. We tested gender-smoking interaction (female versus male effect) by including their product term in the models. Results. When the model included never smoker cases and controls, ORs for categories of pack-years were higher in men, with a negative female-smoking interaction (P=0.0009). Within ever smokers, ORs estimates were somewhat higher in women, but the test for interaction was not significant (P=0.55). We obtained similar results for pack-years as a continuous (log-transformed) variable. Among smokers, no gender-smoking interaction was found by histology. Conclusion. Our findings do not support a higher female susceptibility to tobacco-related lung cancer. Equally vigorous health policy interventions should continue to fight smoking habits in both genders. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 630. doi:1538-7445.AM2012-630

Impact of occupational carcinogens on lung cancer risk in a general population

Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most of the previous studies were in highly exposed industrial cohorts. Our aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population. We applied a new job-exposure matrix (JEM) to translate lifetime work histories, collected by personal interview and coded into standard job titles, into never, low and high exposure levels for six known/suspected occupational lung carcinogens in the Environment and Genetics in Lung cancer Etiology (EAGLE) population-based case-control study, conducted in Lombardy region, Italy, in 2002-05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in men (1537 cases and 1617 controls), by logistic regression adjusted for potential confounders, including smoking and co-exposure to JEM carcinogens. The population attributable fraction (PAF) was estimated as impact measure. Men showed an increased lung cancer risk even at low exposure to asbestos (OR: 1.76; 95% CI: 1.42-2.18), crystalline silica (OR: 1.31; 95% CI: 1.00-1.71) and nickel-chromium (OR: 1.18; 95% CI: 0.90-1.53); risk increased with exposure level. For polycyclic aromatic hydrocarbons, an increased risk (OR: 1.64; 95% CI: 0.99-2.70) was found only for high exposures. The PAFs for any exposure to asbestos, silica and nickel-chromium were 18.1, 5.7 and 7.0%, respectively, equivalent to an overall PAF of 22.5% (95% CI: 14.1-30.0). This corresponds to about 1016 (95% CI: 637-1355) male lung cancer cases/year in Lombardy. These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even at low exposures, in a general population.

GSTM1 and GSTT1 copy numbers and mRNA expression in lung cancer

Large fractions of the human population do not express GSTM1 and GSTT1 (GSTM1/T1) enzymes because of deletions in these genes. These variations affect xenobiotic metabolism and have been evaluated in relation to lung cancer risk, mostly based on null/present gene models. We measured GSTM1/T1 heterozygous deletions, not tested in genome-wide association studies, in 2,120 controls and 2,100 cases from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We evaluated their effect on mRNA expression on lung tissue and peripheral blood samples and their association with lung cancer risk overall and by histology types. We tested the null/present, dominant, and additive models using logistic regression. Cigarette smoking and gender were studied as possible modifiers. Gene expression from blood and lung tissue cells was strongly down regulated in subjects carrying GSTM1/T1 deletions by both trend and dominant models (P < 0.001). In contrast to the null/present model, analyses distinguishing subjects with 0, 1, or 2 GSTM1/T1 deletions revealed several associations. There was a decreased lung cancer risk in never-smokers (OR = 0.44; 95%CI = 0.23-0.82; P = 0.01) and women (OR = 0.50; 95%CI = 0.28-0.90; P = 0.02) carrying 1 or 2 GSTM1 deletions. Analogously, male smokers had an increased risk (OR = 1.13; 95%CI = 1.0-1.28; P = 0.05) and women a decreased risk (OR = 0.78; 95%CI = 0.63-0.97; P = 0.02) for increasing GSTT1 deletions. The corresponding gene smoking and gene-gender interactions were significant (P < 0.05). Our results suggest that decreased activity of GSTM1/T1 enzymes elevates lung cancer risk in male smokers, likely due to impaired carcinogens' detoxification. A protective effect of the same mutations may be operative in never-smokers and women, possibly because of reduced activity of other genotoxic chemicals.

Increased lung cancer risk among bricklayers in an Italian population-based case-control study.

Bricklayers may be at increased risk of lung cancer, although a firm association has not been established. We examined this association within the EAGLE (Environment And Genetics in Lung cancer Etiology) study, a population-based case-control study conducted in Italy between 2002 and 2005. For men in selected occupations in the construction sector we calculated smoking-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). For bricklayers we estimated the population attributable fraction (PAF) and the attributable community risk (ACR). We found increased lung cancer risk for bricklayers (OR 1.57, 95% CI 1.12-2.21; 147 cases, 81 controls). The PAF was 3.5% (95% CI 0.6-6.3), corresponding to an ACR of 3.6 cases annually per 100,000 men (95% CI 0.6-6.6) [corrected] in the whole community. Among bricklayers, there were increased risks for squamous cell (OR 2.03, 95% CI 1.32-3.13, 56 exposed cases) and small cell carcinomas (OR 2.29, 95% CI 1.29-4.07, 21 exposed cases), while no excess (OR 1.06, 95% CI 0.68-1.65, 41 exposed cases) was found for adenocarcinoma. Our findings provide additional evidence of increased lung cancer risk in Italian bricklayers. The association is plausible because they are exposed to several carcinogens, notably crystalline silica.

A Flexible Bayesian Model for Studying Gene–Environment Interaction

An important follow-up step after genetic markers are found to be associated with a disease outcome is a more detailed analysis investigating how the implicated gene or chromosomal region and an established environment risk factor interact to influence the disease risk. The standard approach to this study of gene–environment interaction considers one genetic marker at a time and therefore could misrepresent and underestimate the genetic contribution to the joint effect when one or more functional loci, some of which might not be genotyped, exist in the region and interact with the environment risk factor in a complex way. We develop a more global approach based on a Bayesian model that uses a latent genetic profile variable to capture all of the genetic variation in the entire targeted region and allows the environment effect to vary across different genetic profile categories. We also propose a resampling-based test derived from the developed Bayesian model for the detection of gene–environment interaction. Using data collected in the Environment and Genetics in Lung Cancer Etiology (EAGLE) study, we apply the Bayesian model to evaluate the joint effect of smoking intensity and genetic variants in the 15q25.1 region, which contains a cluster of nicotinic acetylcholine receptor genes and has been shown to be associated with both lung cancer and smoking behavior. We find evidence for gene–environment interaction (P-value = 0.016), with the smoking effect appearing to be stronger in subjects with a genetic profile associated with a higher lung cancer risk; the conventional test of gene–environment interaction based on the single-marker approach is far from significant.