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2.  Are Women Who Smoke at Higher Risk for Lung Cancer Than Men Who Smoke? 
American Journal of Epidemiology  2013;177(7):601-612.
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.
PMCID: PMC3657535  PMID: 23425629
case-control studies; lung cancer; sex differences; smoking
3.  Influence of quercetin-rich food intake on microRNA expression in lung cancer tissues 
Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.
miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR-based analyses, we compared the expression of miRs (n=198) between lung cancer cases consuming high-versus-low quercetin-rich food intake using multivariate ANOVA tests. In family-miR-based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miRs families. We accounted for multiple testing using 10,000 global permutations (significance at p-valueglobal <0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).
Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (p-valueFCS<0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (p-valuesFCS<0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest-and-lowest quercetin-rich food consumers (23 expected by chance; p-valueglobal = 0.047).
We observed differential expression of key biologically functional miRNAs between high-versus-low consumers of quercetin-rich foods in adenocarcinoma cases.
Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis.
PMCID: PMC3538163  PMID: 23035181
4.  GSTM1 and GSTT1 copy numbers and mRNA expression in lung cancer 
Molecular carcinogenesis  2012;51(Suppl 1):E142-E150.
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 2120 controls and 2100 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.
PMCID: PMC3376678  PMID: 22392686
GST; copy numbers; gene expression; lung cancer; smoking and gender differences
5.  A gene expression signature from peripheral whole blood for stage I lung adenocarcinoma 
Affordable early screening in subjects with high risk of lung cancer has great potential to improve survival from this deadly disease. We measured gene expression from lung tissue and peripheral whole blood (PWB) from adenocarcinoma cases and controls to identify dysregulated lung cancer genes that could be tested in blood to improve identification of at-risk patients in the future. Genome-wide mRNA expression analysis was conducted in 153 subjects (73 adenocarcinoma cases, 80 controls) from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using PWB and paired snap-frozen tumor and non-involved lung tissue samples. Analyses were conducted using unpaired t-tests, linear mixed effects and ANOVA models. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the identified biomarkers. We identified 50 dysregulated genes in stage I adenocarcinoma versus control PWB samples (False Discovery Rate ≤0.1, fold change ≥1.5 or ≤0.66). Among them, eight (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor versus non-involved lung tissue samples in stage I cases, suggesting a similar pattern of lung cancer-related changes in PWB and lung tissue. These results were confirmed in two independent gene expression analyses in a blood-based case-control study (n=212) and a tumor-non tumor paired tissue study (n=54). The eight genes discriminated patients with lung cancer from healthy controls with high accuracy (AUC=0.81, 95% CI=0.74–0.87). Our finding suggests the use of gene expression from PWB for the identification of early detection markers of lung cancer in the future.
PMCID: PMC3188352  PMID: 21742797
microarray gene expression; peripheral blood; lung cancer; stage I
6.  Inherited variation at chromosome 12p13.33 including RAD52 influences squamous cell lung carcinoma risk 
Cancer Discovery  2011;2(2):131-139.
While lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies (GWAS) in Europeans have robustly demonstrated only three polymorphic variations influencing lung cancer risk. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a GWAS of 5,355 European smoking lung cancer cases and 4,344 smoking controls, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 SNPs mapping to 917 genes in the HuGE-defined “inflammation” pathway. We identified a susceptibility locus for squamous cell lung carcinoma (SQ) at 12p13.33 (RAD52, rs6489769), and replicated the association in three independent samples totaling 3,359 SQ cases and 9,100 controls (odds ratio=1.20, Pcombined=2.3×10−8).
The combination of pathway-based approaches and information on disease specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases.
PMCID: PMC3354721  PMID: 22585858
Lung cancer; histology; squamous cell carcinoma; pathway analysis; RAD52
8.  Reproductive and hormonal factors and the risk of lung cancer: the EAGLE Study 
Evidence about the role for reproductive and hormonal factors in the etiology of lung cancer in women is conflicting. To clarify this question, we examined 407 female cases and 499 female controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study. Subjects were interviewed in person using a computer-assisted personal interview to assess demographics, education, smoking history, medical history, occupational history, reproductive and hormonal factors. Associations of interest were investigated using logistic regression models, adjusted for catchment area and age (matching variables), cigarette smoking (status, pack-years, and time since quitting). Additional confounding variables were investigated but did not substantially affect the results. We observed a reduced risk of lung cancer among women with later age at first live birth (≥31 years: OR=0.57, 95%CI=0.31–1.06, p-trend=0.05), later age at menopause (≥51 years: OR=0.49, 95%CI=0.31–0.79, p-trend=0.003), and longer reproductive periods (≥41 years: OR=0.44, 95%CI=0.25–0.79, p-trend=0.01). A reduced risk was also observed for Hormone Replacement Therapy (OR=0.63, 95%CI=0.42–0.95, p=0.03) and oral contraceptive use (OR=0.67, 95%CI=0.45–1.00, p=0.05), but no trend with duration of use was detected. Menopausal status (both natural and induced) was associated with an augmented risk. No additional associations were identified for other reproductive variables. This study suggests that women who continue to produce estrogens have a lower lung cancer risk. Large studies with great number of never smoking women, biomarkers of estrogen and molecular classification of lung cancer are needed for a more comprehensive view of the association between reproductive factors and lung cancer risk.
PMCID: PMC3609937  PMID: 23129166
case-control study; lung cancer; reproductive factors
9.  MicroRNA expression differentiates histology and predicts survival of lung cancer 
The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histological subtypes and predict survival for non-small cell lung cancer.
Experimental design
We analyzed miR expression in 165 adenocarcinoma (AD) and 125 squamous cell carcinoma (SQ) tissue samples from the Environmental And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t-tests and F-tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards and survival risk prediction models, accounting for demographic and tumor characteristics.
MiR expression profiles strongly differed between AD and SQ (global p<0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were down-regulated in SQ. Major findings were confirmed by QRT-PCR in EAGLE samples and in an independent set of lung cancer cases. In SQ, low expression of miRs down-regulated in the histology comparison was associated with 1.2 to 3.6-fold increased mortality risk. A 5-miR signature significantly predicted survival for SQ.
We identified a miR expression profile that strongly differentiated AD from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches.
PMCID: PMC3163170  PMID: 20068076
10.  Alcohol Consumption and Lung Cancer Risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study 
American Journal of Epidemiology  2009;171(1):36-44.
The authors investigated the relation between alcohol consumption and lung cancer risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study, a population-based case-control study. Between 2002 and 2005, 2,100 patients with primary lung cancer were recruited from 13 hospitals within the Lombardy region of Italy and were frequency-matched on sex, area of residence, and age to 2,120 randomly selected controls. Alcohol consumption during adulthood was assessed in 1,855 cases and 2,065 controls. Data on lifetime tobacco smoking, diet, education, and anthropometric measures were collected. Adjusted odds ratios and 95% confidence intervals for categories of mean daily ethanol intake were calculated using unconditional logistic regression. Overall, both nondrinkers (odds ratio = 1.42, 95% confidence interval: 1.03, 2.01) and very heavy drinkers (≥60 g/day; odds ratio = 1.44, 95% confidence interval: 1.01, 2.07) were at significantly greater risk than very light drinkers (0.1–4.9 g/day). The alcohol effect was modified by smoking behavior, with no excess risk being observed in never smokers. In summary, heavy alcohol consumption was a risk factor for lung cancer among smokers in this study. Although residual confounding by tobacco smoking cannot be ruled out, this finding may reflect interplay between alcohol and smoking, emphasizing the need for preventive measures.
PMCID: PMC2800301  PMID: 19933698
alcohol drinking; case-control studies; ethanol; lung neoplasms; risk factors; smoking
11.  Family history of cancer and non-malignant lung diseases as risk factors for lung cancer 
Family history (FH) of lung cancer is an established risk factor for lung cancer, but the modifying effect of smoking in relatives has been rarely examined. Also, the role of FH of non-malignant lung diseases on lung cancer risk is not well known. We examined the role of FH of cancer and FH of non-malignant lung diseases in lung cancer risk, overall, and by personal smoking, FH of smoking, and histology in 1,946 cases and 2,116 population-based controls within the Environment And Genetics in Lung cancer Etiology (EAGLE) study. Odds ratios (ORs) and 95% CI from logistic regression were calculated adjusting for age, gender, residence, education, and cigarette smoking. FH of lung cancer in any family member was associated with increased lung cancer risk (OR = 1.57, 95% CI = 1.25–1.98). The odds associated with fathers’, mothers’ and siblings’ history of lung cancer were 1.41, 2.14, and 1.53, respectively. The associations were generally stronger in never smokers, younger subjects, and for the adenocarcinoma and squamous cell carcinoma subtypes. FH of chronic bronchitis and pneumonia were associated with increased (OR =1.49, 95% CI = 1.23–1.80) and decreased (OR = 0.73, 95% CI = 0.61–0.87) lung cancer risk, respectively. FH of lung cancer and FH of non-malignant lung diseases affected lung cancer risk independently, and did not appear to be modified by FH of smoking.
PMCID: PMC2865851  PMID: 19350630
family history; lung cancer; smoking; chronic bronchitis; pneumonia
12.  Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma‐prone families from three continents 
Journal of Medical Genetics  2006;44(2):99-106.
The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer.
These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.
Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk.
The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.
PMCID: PMC2598064  PMID: 16905682
melanoma;  CDKN2A ; multiple primary melanomas; pancreatic cancer
13.  Intakes of red meat, processed meat, and meat-mutagens increase lung cancer risk 
Cancer research  2009;69(3):932-939.
Red and processed meat intake may increase lung cancer risk. However, the epidemiologic evidence is inconsistent and few studies have evaluated the role of meat-mutagens formed during high cooking temperatures. We investigated the association of red meat, processed meat, and meat-mutagen intake with lung cancer risk in Environment And Genetics in Lung cancer Etiology (EAGLE), a population-based case-control study. Primary lung cancer cases (n=2101) were recruited from 13 hospitals within the Lombardy region of Italy examining ~80% of the cases from the area. Non-cancer population controls (n=2120), matched to cases on gender, residence, and age, were randomly selected from the same catchment area. Diet was assessed in 1903 cases and 2073 controls, and used in conjunction with a meat-mutagen database to estimate intake of heterocyclic amines and benzo[a]pyrene. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific tertiles of intake were calculated using unconditional logistic regression. Red and processed meat were positively associated with lung cancer risk (highest-versus-lowest tertile: OR=1.8; 95% CI=1.5–2.2; p-trend<0.001 and OR=1.7; 95% CI=1.4–2.1; p-trend<0.001, respectively); the risks were strongest among never smokers (OR=2.4, 95% CI=1.4–4.0, p-trend=0.001 and OR=2.5, 95% CI=1.5–4.2, p-trend=0.001, respectively). Heterocyclic amines and benzo[a]pyrene were significantly associated with increased risk of lung cancer. When separated by histology, significant positive associations for both meat groups were restricted to adenocarcinoma and squamous cell carcinoma, but not small cell carcinoma of the lung. In summary, red meat, processed meat, and meat-mutagens were independently associated with increased risk of lung cancer.
PMCID: PMC2720759  PMID: 19141639
red meat; processed meat; meat-mutagens; cooking methods; lung cancer
14.  Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer 
Cancer research  2013;73(7):2211-2220.
Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to evaluate the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for US-males aged 50-years. Six out of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P=7×10-4) and UGT1A6 (P=8×10-4). The 30-year absolute risk of bladder cancer in US males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile, compared to 2,000 cases prevented by a similar effort in the lowest PRS quartile (P-additive =1×10-4). The impact of eliminating smoking the on number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made.
PMCID: PMC3688270  PMID: 23536561
15.  Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia 
Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.
We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non–lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10–5 was used to assign statistical significance.
The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10–6). This association was strongest for women with adenocarcinoma (P = 1.2×10–4) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10–8) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10–5), respectively.
Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
PMCID: PMC3982896  PMID: 24681604
16.  Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking 
Stephens, Sarah H. | Hartz, Sarah M. | Hoft, Nicole R. | Saccone, Nancy L. | Corley, Robin C. | Hewitt, John K. | Hopfer, Christian J. | Breslau, Naomi | Coon, Hilary | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Han, Younghun | Hansel, Nadia N. | Jiang, Chenhui | Korhonen, Tellervo | Lind, Penelope A. | Liu, Jason | Lyytikäinen, Leo-Pekka | Michel, Martha | Shaffer, John R. | Short, Susan E. | Sun, Juzhong | Teumer, Alexander | Thompson, John R. | Vogelzangs, Nicole | Vink, Jacqueline M. | Wenzlaff, Angela | Wheeler, William | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri H. | Benjamin, Daniel J. | Bergen, Andrew W. | Broms, Ulla | Cesarini, David | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gillespie, Nathan A. | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Heikkilä, Kauko | Hickie, Ian B. | Hottenga, Jouke Jan | Jousilahti, Pekka | Kaakinen, Marika | Kähönen, Mika | Koellinger, Philipp D. | Kittner, Stephen | Konte, Bettina | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Murray, Tanda | Nauck, Matthias | North, Kari E. | Paré, Peter D. | Pergadia, Michele | Ruczinski, Ingo | Salomaa, Veikko | Viikari, Jorma | Willemsen, Gonneke | Barnes, Kathleen C. | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Edenberg, Howard J. | Francks, Clyde | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Johannesson, Magnus | Kendler, Kenneth S. | Lehtimäki, Terho | Magnusson, Patrik K.E. | Marazita, Mary L. | Marchini, Jonathan | Mitchell, Braxton D. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Schwartz, Ann G. | Shete, Sanjay | Spitz, Margaret | Swan, Gary E. | Völzke, Henry | Veijola, Juha | Wei, Qingyi | Amos, Chris | Cannon, Dale S. | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J. | Ehringer, Marissa A.
Genetic epidemiology  2013;37(8):846-859.
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
PMCID: PMC3947535  PMID: 24186853
CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke
17.  Genome-wide Association Study Identifies Two Susceptibility Loci for Osteosarcoma 
Nature genetics  2013;45(7):799-803.
Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. In order to better understand the genetic etiology of osteosarcoma, we performed a multi-stage genome-wide association study (GWAS) consisting of 941 cases and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: rs1906953 at 6p21.3, in the glutamate receptor metabotropic 4 [GRM4] gene (P = 8.1 ×10-9), and rs7591996 and rs10208273 in a gene desert on 2p25.2 (P = 1.0 ×10-8 and 2.9 ×10-7). These two susceptibility loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
PMCID: PMC3910497  PMID: 23727862
19.  A regression model for risk difference estimation in population-based case–control studies clarifies gender differences in lung cancer risk of smokers and never smokers 
Additive risk models are necessary for understanding the joint effects of exposures on individual and population disease risk. Yet technical challenges have limited the consideration of additive risk models in case–control studies.
Using a flexible risk regression model that allows additive and multiplicative components to estimate absolute risks and risk differences, we report a new analysis of data from the population-based case–control Environment And Genetics in Lung cancer Etiology study, conducted in Northern Italy between 2002–2005. The analysis provides estimates of the gender-specific absolute risk (cumulative risk) for non-smoking- and smoking-associated lung cancer, adjusted for demographic, occupational, and smoking history variables.
In the multiple-variable lexpit regression, the adjusted 3-year absolute risk of lung cancer in never smokers was 4.6 per 100,000 persons higher in women than men. However, the absolute increase in 3-year risk of lung cancer for every 10 additional pack-years smoked was less for women than men, 13.6 versus 52.9 per 100,000 persons.
In a Northern Italian population, the absolute risk of lung cancer among never smokers is higher in women than men but among smokers is lower in women than men. Lexpit regression is a novel approach to additive-multiplicative risk modeling that can contribute to clearer interpretation of population-based case–control studies.
PMCID: PMC3840559  PMID: 24252624
Additive risk; Absolute risk; Case–control study; EAGLE; Lung cancer; Risk assessment; Sex factors; Smoking
20.  Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk 
Cancer  2012;118(22):5630-5636.
Pulmonary inflammation may contribute to lung cancer etiology. We conducted a broad evaluation of the association of single nucleotide polymorphisms (SNPs) in innate immunity and inflammation pathways with lung cancer risk, and conducted comparisons with a lung cancer genome wide association study (GWAS).
We included 378 lung cancer cases and 450 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. An Illumina GoldenGate oligonucleotide pool assay was used to genotype 1,429 SNPs. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for each SNP, and p-values for trend were calculated. For statistically significant SNPs (p-trend<0.05), we replicated our results with genotyped or imputed SNPs in the GWAS, and adjusted p-values for multiple testing.
In our PLCO analysis, we observed a significant association between 81 SNPs located in 44 genes and lung cancer (p-trend<0.05). Of these 81 SNPS, there was evidence for confirmation in the GWAS for 10 SNPs. However, after adjusting for multiple comparisons, the only SNP that remained significantly associated with lung cancer in the replication phase was rs4648127 (NFKB1; multiple testing adjusted p-trend=0.02). The CT/TT genotype of NFKB1 was associated with reduced odds of lung cancer in the PLCO study (OR=0.56; 95% CI 0.37–0.86) and the GWAS (OR=0.79; 95% CI 0.69–0.90).
We found a significant association between a variant in the NFKB1 gene and lung cancer risk. Our findings add to evidence implicating inflammation and immunity in lung cancer etiology.
PMCID: PMC3485420  PMID: 23044494
lung cancer; genetics; inflammation; immunity; epidemiology
21.  A variant in FTO shows association with melanoma risk not due to BMI 
Iles, Mark M | Law, Matthew H | Stacey, Simon N | Han, Jiali | Fang, Shenying | Pfeiffer, Ruth | Harland, Mark | MacGregor, Stuart | Taylor, John C | Aben, Katja K | Akslen, Lars A | Avril, Marie-Françoise | Azizi, Esther | Bakker, Bert | Benediktsdottir, Kristrun R | Bergman, Wilma | Scarrà, Giovanna Bianchi | Brown, Kevin M | Calista, Donato | Chaudru, Valerié | Fargnoli, Maria Concetta | Cust, Anne E | Demenais, Florence | de Waal, Anne C | Dębniak, Tadeusz | Elder, David E | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Gillanders, Elizabeth M | Goldstein, Alisa M | Gruis, Nelleke A | Hansson, Johan | Helsing, Per | Hočevar, Marko | Höiom, Veronica | Hopper, John L | Ingvar, Christian | Janssen, Marjolein | Jenkins, Mark A | Kanetsky, Peter A | Kiemeney, Lambertus A | Lang, Julie | Lathrop, G Mark | Leachman, Sancy | Lee, Jeffrey E | Lubiński, Jan | Mackie, Rona M | Mann, Graham J | Mayordomo, Jose I | Molven, Anders | Mulder, Suzanne | Nagore, Eduardo | Novaković, Srdjan | Okamoto, Ichiro | Olafsson, Jon H | Olsson, Håkan | Pehamberger, Hubert | Peris, Ketty | Grasa, Maria Pilar | Planelles, Dolores | Puig, Susana | Puig-Butille, Joan Anton | Randerson-Moor, Juliette | Requena, Celia | Rivoltini, Licia | Rodolfo, Monica | Santinami, Mario | Sigurgeirsson, Bardur | Snowden, Helen | Song, Fengju | Sulem, Patrick | Thorisdottir, Kristin | Tuominen, Rainer | Van Belle, Patricia | van der Stoep, Nienke | van Rossum, Michelle M | Wei, Qingyi | Wendt, Judith | Zelenika, Diana | Zhang, Mingfeng | Landi, Maria Teresa | Thorleifsson, Gudmar | Bishop, D Timothy | Amos, Christopher I | Hayward, Nicholas K | Stefansson, Kari | Bishop, Julia A Newton | Barrett, Jennifer H
Nature genetics  2013;45(4):428-432.
We report the results of an association study of melanoma based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed a novel association between several single nucleotide polymorphisms (SNPs) in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined p=3.6×10−12, per-allele OR for A=1.16). As well as identifying a novel melanoma susceptibility locus, this is the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and show no association with BMI. This suggests FTO’s function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
PMCID: PMC3640814  PMID: 23455637
22.  Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies 
Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. Using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% CI 74.8-143.2) for SqCC, 111.3 (95% CI 69.8-177.5) for SCLC, and 21.9 (95% CI 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI 31.5-124.6), 108.6 (95% CI 50.7-232.8), and 16.8 (95% CI 9.2-30.6), respectively. Whereas ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.
PMCID: PMC3296911  PMID: 22052329
cigarette smoking; lung cancer; relative risk characterization; tobacco smoke; stem cells
23.  Increased Genetic Vulnerability to Smoking at CHRNA5 in Early-Onset Smokers 
Hartz, Sarah M. | Short, Susan E. | Saccone, Nancy L. | Culverhouse, Robert | Chen, LiShiun | Schwantes-An, Tae-Hwi | Coon, Hilary | Han, Younghun | Stephens, Sarah H. | Sun, Juzhong | Chen, Xiangning | Ducci, Francesca | Dueker, Nicole | Franceschini, Nora | Frank, Josef | Geller, Frank | Guđbjartsson, Daniel | Hansel, Nadia N. | Jiang, Chenhui | Keskitalo-Vuokko, Kaisu | Liu, Zhen | Lyytikäinen, Leo-Pekka | Michel, Martha | Rawal, Rajesh | Hum, Sc | Rosenberger, Albert | Scheet, Paul | Shaffer, John R. | Teumer, Alexander | Thompson, John R. | Vink, Jacqueline M. | Vogelzangs, Nicole | Wenzlaff, Angela S. | Wheeler, William | Xiao, Xiangjun | Yang, Bao-Zhu | Aggen, Steven H. | Balmforth, Anthony J. | Baumeister, Sebastian E. | Beaty, Terri | Bennett, Siiri | Bergen, Andrew W. | Boyd, Heather A. | Broms, Ulla | Campbell, Harry | Chatterjee, Nilanjan | Chen, Jingchun | Cheng, Yu-Ching | Cichon, Sven | Couper, David | Cucca, Francesco | Dick, Danielle M. | Foroud, Tatiana | Furberg, Helena | Giegling, Ina | Gu, Fangyi | Hall, Alistair S. | Hällfors, Jenni | Han, Shizhong | Hartmann, Annette M. | Hayward, Caroline | Heikkilä, Kauko | Lic, Phil | Hewitt, John K. | Hottenga, Jouke Jan | Jensen, Majken K. | Jousilahti, Pekka | Kaakinen, Marika | Kittner, Steven J. | Konte, Bettina | Korhonen, Tellervo | Landi, Maria-Teresa | Laatikainen, Tiina | Leppert, Mark | Levy, Steven M. | Mathias, Rasika A. | McNeil, Daniel W. | Medland, Sarah E. | Montgomery, Grant W. | Muley, Thomas | Murray, Tanda | Nauck, Matthias | North, Kari | Pergadia, Michele | Polasek, Ozren | Ramos, Erin M. | Ripatti, Samuli | Risch, Angela | Ruczinski, Ingo | Rudan, Igor | Salomaa, Veikko | Schlessinger, David | Styrkársdóttir, Unnur | Terracciano, Antonio | Uda, Manuela | Willemsen, Gonneke | Wu, Xifeng | Abecasis, Goncalo | Barnes, Kathleen | Bickeböller, Heike | Boerwinkle, Eric | Boomsma, Dorret I. | Caporaso, Neil | Duan, Jubao | Edenberg, Howard J. | Francks, Clyde | Gejman, Pablo V. | Gelernter, Joel | Grabe, Hans Jörgen | Hops, Hyman | Jarvelin, Marjo-Riitta | Viikari, Jorma | Kähönen, Mika | Kendler, Kenneth S. | Lehtimäki, Terho | Levinson, Douglas F. | Marazita, Mary L. | Marchini, Jonathan | Melbye, Mads | Mitchell, Braxton D. | Murray, Jeffrey C. | Nöthen, Markus M. | Penninx, Brenda W. | Raitakari, Olli | Rietschel, Marcella | Rujescu, Dan | Samani, Nilesh J. | Sanders, Alan R. | Schwartz, Ann G. | Shete, Sanjay | Shi, Jianxin | Spitz, Margaret | Stefansson, Kari | Swan, Gary E. | Thorgeirsson, Thorgeir | Völzke, Henry | Wei, Qingyi | Wichmann, H.-Erich | Amos, Christopher I. | Breslau, Naomi | Cannon, Dale S. | Ehringer, Marissa | Grucza, Richard | Hatsukami, Dorothy | Heath, Andrew | Johnson, Eric O. | Kaprio, Jaakko | Madden, Pamela | Martin, Nicholas G. | Stevens, Victoria L. | Stitzel, Jerry A. | Weiss, Robert B. | Kraft, Peter | Bierut, Laura J.
Archives of general psychiatry  2012;69(8):854-860.
Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.
To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.
Data Sources
Primary data.
Study Selection
Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.
Data Extraction
Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.
Data Synthesis
Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36–1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21–1.33, n = 19 505) (P = .01).
These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
PMCID: PMC3482121  PMID: 22868939
24.  Impact of occupational carcinogens on lung cancer risk in a general population 
Background 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.
Methods 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.
Results 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.
Conclusions These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even at low exposures, in a general population.
PMCID: PMC3396321  PMID: 22467291
lung neoplasms; case–control study; carcinogens; occupational health
25.  Exomic Sequencing to Identify Germline Variants in Familial Melanoma 
Germlines are the source of DNA in all cells. A mutation at the germline level is the first step to developing cancer, and the vast majority of cancer is genetic. Melanoma, the leading cause of skin cancer death, is known to be highly heritable and rare. Using a family model, high risk variants related to melanoma can be identified. The goal of the study is to integrate information from sequencing, epigenetics, and expression to identify functional and regulatory genes that are associated with melanoma. Families with two or more 1st degree relatives with melanoma were considered at high risk and were investigated in this study. Initially, sequencing data of families with 3 or more relatives with the disease were examined and shared DNA variants were selected for further examination. Genetic databases and annotation tools were used to identify genes based on their known gene function and regulation, pathways, and variant conservation. Gene browsers were also used to identify any histone markers, DNA methylation sites, and other epigenetic indicators. Based on our candidate genes, there is a possibility of genetic heterogeneity, in which multiple genes may be responsible for disease susceptibility. Selected candidate genes will undergo fine mapping to further investigate the region and replication in additional families and population studies of melanoma.
PMCID: PMC3635265

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