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Background: Smoking cessation reduces lung cancer mortality. However, little is known about whether diagnosis of lung cancer impacts changes in smoking behaviors. Furthermore, the effects of smoking cessation on the risk of second primary lung cancer (SPLC) have not been established yet. This study aims to examine smoking behavior changes after initial primary lung cancer (IPLC) diagnosis and estimate the effect of smoking cessation on SPLC risk following IPLC diagnosis., Methods: The study cohort consisted of 986 participants in the Multiethnic Cohort Study who were free of lung cancer and active smokers at baseline (1993-1996), provided 10-year follow-up smoking data (2003-2008), and were diagnosed with IPLC in 1993-2017. The primary outcome was a change in smoking status from "current" at baseline to "former" at 10-year follow-up (ie, smoking cessation), analyzed using logistic regression. The second outcome was SPLC incidence after smoking cessation, estimated using cause-specific Cox regression. All statistical tests were 2-sided., Results: Among 986 current smokers at baseline, 51.1% reported smoking cessation at 10-year follow-up. The smoking cessation rate was statistically significantly higher (80.6%) for those diagnosed with IPLC between baseline and 10-year follow-up vs those without IPLC diagnosis (45.4%) during the 10-year period (adjusted odds ratio = 5.12, 95% confidence interval [CI] = 3.38 to 7.98; P  <   .001). Incidence of SPLC was statistically significantly lower among the 504 participants who reported smoking cessation at follow-up compared with those without smoking cessation (adjusted hazard ratio = 0.31, 95% CI = 0.14 to 0.67; P  =   .003)., Conclusion: Lung cancer diagnosis has a statistically significant impact on smoking cessation. Quitting smoking after IPLC diagnosis may reduce the risk of developing a subsequent malignancy in the lungs., (© The Author(s) 2021. Published by Oxford University Press.)

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10 -8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10 -9 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention., (©2021 American Association for Cancer Research.)

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10 -4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR MVMR = 1.28, 95% CI = 1.06-1.55, P MVMR = .011), and an inverse effect on lung adenocarcinoma (OR MVMR = 0.86, 95% CI = 0.77-0.96, P MVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR UVMR = 1.19, 95% CI = 1.01-1.40, P UVMR = .036), but this effect disappeared after adjustment of smoking (OR MVMR = 1.02, 95% CI = 0.90-1.16, P MVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer., (© 2020 UICC.)

Introduction: Cyanoethyl mercapturic acid (CEMA) is a urinary metabolite of acrylonitrile, a toxicant found in substantial quantities in cigarette smoke, but not in non-combusted products such as e-cigarettes or smokeless tobacco and rarely in the diet or in the general human environment. Thus, we hypothesized that CEMA is an excellent biomarker of combusted tobacco product use., Aims and Methods: We tested this hypothesis by analyzing CEMA in the urine of 1259 cigarette smokers (urinary cotinine ≥25 ng/mL) and 1191 nonsmokers. The analyses of CEMA and cotinine were performed by validated liquid chromatography-tandem mass spectrometry methods. Logistic regression was fit for log-transformed CEMA to construct the receiver operating characteristic curve., Results: We found that a CEMA cutpoint of 27 pmol/mL urine differentiated cigarette smokers from nonsmokers with sensitivity and specificity greater than 99%. The use of different cotinine cutpoints to define smokers (10-30 ng/mL) had little effect on the results., Conclusions: CEMA is a highly reliable urinary biomarker to identify users of combusted tobacco products such as cigarettes as opposed to users of non-combusted products, medicinal nicotine, or nonusers of tobacco products., Implications: CEMA can be used to distinguish users of combusted tobacco products from non-combusted products such as e-cigarettes, smokeless tobacco, and medicinal nicotine. Levels of CEMA in the urine of people who use these non-combusted products are extremely low, in contrast to cotinine., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We previously found that African Americans and Native Hawaiians were at highest lung cancer risk compared with Japanese Americans and Latinos; whites were midway in risk. These differences were more evident at relatively low levels of smoking intensity, fewer than 20 cigarettes per day (CPD), than at higher intensity., Methods: We apportioned lung cancer risk into three parts: age-specific background risk (among never smokers), an excess relative risk term for cumulative smoking, and modifiers of the smoking effect: race and years-quit smoking. We also explored the effect of replacing self-reports of CPD with a urinary biomarker-total nicotine equivalents-using data from a urinary biomarker substudy., Results: Total lung cancers increased from 1979 to 4993 compared to earlier analysis. Estimated excess relative risks for lung cancer due to smoking for 50 years at 10 CPD (25 pack-years) ranged from 21.9 (95% CI = 18.0 to 25.8) for Native Hawaiians to 8.0 (95% CI = 6.6 to 9.4) for Latinos over the five groups. The risk from smoking was higher for squamous cell carcinomas and small cell cancers than for adenocarcinomas. Racial differences consistent with earlier patterns were seen for overall cancer and for cancer subtypes. Adjusting for predicted total nicotine equivalents, Japanese Americans no longer exhibit a lower risk, and African Americans are no longer at higher risk, compared to whites. Striking risk differences between Native Hawaiians and Latinos persist., Conclusions: Racial differences in lung cancer risk persist in the Multiethnic Cohort study that are not easily explained by variations in self-reported or urinary biomarker-measured smoking intensities., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The purpose of this study was to examine if the smoking-related higher breast cancer risk was similar for the five race/ethnicity groups in the Multiethnic Cohort (MEC) study and by oestrogen (ER) and progesterone (PR) receptor status., Methods: From 1993 to 2013, we followed 67 313 women who were enrolled in the MEC study at 45-75 years of age. We identified breast cancer cases and tumour receptor status via linkage to the Hawaii and California Surveillance, Epidemiology and End Results Program cancer registries through December 2013. We used Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios with 95% confidence intervals (CI)., Results: During a mean follow-up of 16.7 years, we identified 4230 incident, invasive breast cancer cases. Compared with parous never smokers, parous ever smokers who had smoked more than 5 years before their first live childbirth had a higher risk of breast cancer overall of 31% (95% CI: 1.14-1.51). This higher risk was 51% (95% CI: 1.05-2.16) for African Americans, 66% (95% CI: 1.10-2.50) for Native Hawaiians, 42% (95% CI: 1.13-1.78) for Whites, 37% (95% CI: 1.17-1.61) for ER-positive (ER+) tumours and 33% (95% CI: 1.11-1.59) for PR+ tumours. No difference was suggested by racial/ethnic groups (Pheterogeneity = 0.15) or tumour receptor status (Pheterogeneity = 0.60 by ER status and 0.95 by PR status)., Conclusions: We find that the higher breast cancer risk related to smoking is similar across racial/ethnic groups and by ER and PR status, indicating that breast cancer should be considered as a smoking-related cancer., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Lung cancer is the leading cause of cancer-related death. While cigarette smoking is the primary cause of this malignancy, risk differs across racial/ethnic groups. For the same number of cigarettes smoked, Native Hawaiians compared to whites are at greater risk and Japanese Americans are at lower risk of developing lung cancer. DNA methylation of specific CpG sites (e.g., in AHRR and F2RL3) is the most common blood epigenetic modification associated with smoking status. However, the influence of internal smoking dose, measured by urinary nicotine equivalents (NE), on DNA methylation in current smokers has not been investigated, nor has a study evaluated whether for the same smoking dose, circulating leukocyte DNA methylation patterns differ by race., Methods: We conducted an epigenome-wide association study (EWAS) of NE in 612 smokers from three racial/ethnic groups: whites (n = 204), Native Hawaiians (n = 205), and Japanese Americans (n = 203). Genome-wide DNA methylation profiling of blood leukocyte DNA was measured using the Illumina 450K BeadChip array. Average β value, the ratio of signal from a methylated probe relative to the sum of the methylated and unmethylated probes at that CpG, was the dependent variables in linear regression models adjusting for age, sex, race (for pan-ethnic analysis), and estimated cell-type distribution., Results: We found that NE was significantly associated with six differentially methylated CpG sites (Bonferroni corrected p < 1.48 × 10-7): four in or near the FOXK2, PBX1, FNDC7, and FUBP3 genes and two in non-annotated genetic regions. Higher levels of NE were associated with increasing methylation beta-valuesin all six sites. For all six CpG sites, the association was only observed in Native Hawaiians, suggesting that the influence of smoking dose on DNA methylation patterns is heterogeneous across race/ethnicity (p interactions < 8.8 × 10-8). We found two additional CpG sites associated with NE in only Native Hawaiians., Conclusions: In conclusion, internal smoking dose was associated with increased DNA methylation in circulating leukocytes at specific sites in Native Hawaiian smokers but not in white or Japanese American smokers.

Whether women are more susceptible than men to smoking-related lung cancer has been a topic of controversy. To address this question, we compared risks of lung cancer associated with smoking by sex. Altogether, 585,583 participants from 3 Norwegian cohorts (Norwegian Counties Study, 40 Years Study, and Cohort of Norway (CONOR) Study) were followed until December 31, 2013, through linkage of data to national registries. We used Cox proportional hazards models and 95% confidence intervals to estimate risks. During nearly 12 million person-years of follow-up, 6,534 participants (43% women) were diagnosed with lung cancer. More men than women were heavier smokers. Compared with never smokers, male and female current smokers with ≥16 pack-years of smoking had hazard ratios for lung cancer of 27.24 (95% confidence interval (CI): 22.42, 33.09) and 23.90 (95% CI: 20.57, 27.76), respectively (P for heterogeneity = 0.30). In contrast, for current smokers, in a model with pack-years measured continuously, men had a hazard ratio of 1.43 (95% CI: 1.39, 1.48) and women a hazard ratio of 1.64 (95% CI: 1.57, 1.71) for each 10-pack-year increment of smoking (P for heterogeneity < 0.01). Our results suggest that women have an increased susceptibility to lung cancer compared with men, given the same lifetime smoking exposure.

Objective: To explore whether airway obstruction is associated with HIV in a cohort of HIV-infected and uninfected smokers., Methods: People living with HIV (PLWHIV) participated in the ANRS EP48 HIV CHEST study, an early lung cancer diagnosis study with low-dose chest tomography. HIV-uninfected study participants were from the CONSTANCES cohort. Inclusion criteria were an age greater than 40 years, a smoking history of at least 20 pack-years, and for PLWHIV, a CD4 T-lymphocyte nadir less than 350/μl and last CD4 cell count more than 100 cells/μl. Two randomly selected HIV-uninfected study participants were matched by age and sex with one PLWHIV. Prebronchodilatator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio was the primary outcome, and association of FEV1/FVC ratio less than 0.70 and FEV1 less than 80% of the theoretical value, as a proxy of chronic obstructive pulmonary disease, the secondary outcome., Results: In total, 351 PLWHIV and 702 HIV-uninfected study participants were included. Median age was 50 years, and 17% of study participants were women. Plasma HIV RNA was less than 50 copies/ml in 89% of PLWHIV, with a median CD4 cell count of 573 cells/μl. HIV (β -2.19), age (per 10 years increase; β -2.81), tobacco use (per 5 pack-years increase; β -0.34), and hepatitis C virus serology (β-2.50) were negatively associated with FEV1/FVC. HIV [odds ratio (OR: 1.72)], age (per 10 years increase; OR 1.77), and tobacco use (per 5 pack-years increase; OR 1.11) were significantly associated with the secondary outcome., Conclusion: Our study found a significant association of airway obstruction with HIV status in smokers aged more than 40 years with previous immunodeficiency.

Background: 1,3-Butadiene (BD) is an important carcinogen in tobacco smoke that undergoes metabolic activation to DNA-reactive epoxides. These species can be detoxified via glutathione conjugation and excreted in urine as the corresponding N-acetylcysteine conjugates. We hypothesize that single nucleotide polymorphisms (SNPs) in BD-metabolizing genes may change the balance of BD bioactivation and detoxification in White, Japanese American, and African American smokers, potentially contributing to ethnic differences in lung cancer risk. Methods: We measured the levels of BD metabolites, 1- and 2-( N -acetyl-L-cysteine-S-yl)-1-hydroxybut-3-ene (MHBMA) and N -acetyl- S -(3,4-dihydroxybutyl)-L-cysteine (DHBMA), in urine samples from a total of 1,072 White, Japanese American, and African American smokers and adjusted these values for body mass index, age, batch, and total nicotine equivalents. We also conducted a genome-wide association study to identify genetic determinants of BD metabolism. Results: We found that mean urinary MHBMA concentrations differed significantly by ethnicity ( P = 4.0 × 10 -25 ). African Americans excreted the highest levels of MHBMA followed by Whites and Japanese Americans. MHBMA levels were affected by GSTT1 gene copy number ( P < 0.0001); conditional on GSTT1 , no other polymorphisms showed a significant association. Urinary DHBMA levels also differed between ethnic groups ( P = 3.3 × 10 -4 ), but were not affected by GSTT1 copy number ( P = 0.226). Conclusions: GSTT1 gene deletion has a strong effect on urinary MHBMA levels, and therefore BD metabolism, in smokers. Impact: Our results show that the order of MHBMA levels among ethnic groups is consistent with their respective lung cancer risk and can be partially explained by GSTT1 genotype. Cancer Epidemiol Biomarkers Prev; 26(7); 1034-42. ©2017 AACR ., (©2017 American Association for Cancer Research.)

While smoking is the primary cause of lung cancer, only 11-24% of smokers develop the malignancy over their lifetime. The primary addictive agent in tobacco smoke is nicotine and variation in nicotine metabolism may influence the smoking levels of an individual. Therefore, inter-individual variation in lung cancer risk among smokers may be due in part to differences in the activity of enzymes involved in nicotine metabolism. In most smokers, cytochrome P450 2A6 (CYP2A6)-catalyzed C-oxidation accounts for >75% of nicotine metabolism, and the activity of this enzyme has been shown to correlate with the amount of nicotine and carcinogens drawn from cigarettes. We prospectively evaluated the association of urinary biomarkers of nicotine uptake (total nicotine equivalents [TNE]) and CYP2A6 activity (ratio of urinary total trans-3'-hydroxycotinine to cotinine) with lung cancer risk among 2,309 Multiethnic Cohort Study participants who were current smokers at time of urine collection; 92 cases were diagnosed during a mean follow-up of 9.5 years. We found that higher CYP2A6 activity and TNE was associated with increased lung cancer risk after adjusting for age, sex, race/ethnicity, body mass index, smoking duration, and urinary creatinine (p's = 0.002). The association for CYP2A6 activity remained even after adjusting for self-reported cigarettes per day (CPD) (Hazard Ratio [HR] per unit increase in log-CYP2A6 activity = 1.52; p = 0.005) and after adjusting for TNE (HR = 1.46; p = 0.01). In contrast, the association between TNE and lung cancer risk was of borderline statistical significance when adjusted for CPD (HR = 1.53; p = 0.06) and not statistically significant when further adjusted for CYP2A6 activity (HR = 1.30; p = 0.22). These findings suggest that CYP2A6 activity provides information on lung cancer risk that is not captured by smoking history or a (short-term) biomarker of dose. CYP2A6 activity should be further studied as a risk biomarker for smoking-related lung cancer.

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversely associated with lung cancer risk with evidence most strongly supporting lower risk for light and moderate drinkers relative to non-drinkers (>0-4.9 g per day: OR = 0.80, 95% CI = 0.70-0.90; 5-9.9 g per day: OR = 0.82, 95% CI = 0.69-0.99; 10-19.9 g per day: OR = 0.79, 95% CI = 0.65-0.96). Inverse associations were found for consumption of wine and liquor, but not beer. The results indicate that alcohol consumption is inversely associated with lung cancer risk, particularly among subjects with low to moderate consumption levels, and among wine and liquor drinkers, but not beer drinkers. Although our results should have no relevant bias from the confounding effect of smoking we cannot preclude that confounding by other factors contributed to the observed associations. Confounding in relation to the non-drinker reference category may be of particular importance., (© 2017 UICC.)

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk., Competing Interests: The authors have declared that no competing interests exist.

Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3'-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10 -8 ). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768-76. ©2016 AACR., Competing Interests: Statement We confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (©2016 American Association for Cancer Research.)

Background: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not., Methods: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium., Results: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10 -10 ). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype., Conclusion: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke., (Copyright © 2016 Forschungsgesellschaft für Arbeitsphysiologie und Arbeitschutz e.V. Published by Elsevier B.V. All rights reserved.)

Objectives: We conducted a prospective analysis of 145,886 participants in the multiethnic cohort to examine the relationship of alcohol drinking and smoking with pancreatitis., Methods: Pancreatitis cases were categorized as gallstone-related acute pancreatitis (GSAP) (N = 1,065), non-GSAP (N = 1,222), and recurrent acute (RAP)/chronic pancreatitis (CP) (N = 523). We used the baseline questionnaire to identify alcohol intake and smoking history. Associations were estimated by hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox models., Results: Cigarette smoking was associated with non-GSAP and RAP/CP. Moderate alcohol intake was inversely associated with all types of pancreatitis in women (HRs, 0.66 to 0.81 for <1 drink per day), and with RAP/CP in men (HR, 0.57; 95% CI, 0.41-0.79 for <2 drinks per day). The risk of non-GS pancreatitis associated with current smoking was highest among men who consumed more than 4 drinks per day (HR, 2.06; 95% CI, 1.28-3.30), whereas among never smokers, moderate drinking was associated with a reduced risk (HR, 0.70; 95% CI, 0.51-0.96). In women, drinking less than 2 drinks per day was associated with a reduced risk of GSAP among never smokers (HR, 0.61; 95% CI, 0.46-0.80)., Conclusions: Smoking is a risk factor for non-GS pancreatitis. Moderate alcohol intake is protective against all types of pancreatitis in women and against RAP/CP in men.

Results from the Multiethnic Cohort Study demonstrated significant differences in lung cancer risk among cigarette smokers from five different ethnic/racial groups. For the same number of cigarettes smoked, and particularly among light smokers, African Americans and Native Hawaiians had the highest risk for lung cancer, Whites had intermediate risk, while Latinos and Japanese Americans had the lowest risk. We analyzed urine samples from 331-709 participants from each ethnic group in this study for metabolites of phenanthrene, a surrogate for carcinogenic polycyclic aromatic hydrocarbon exposure. Consistent with their lung cancer risk and our previous studies of several other carcinogens and toxicants of cigarette smoke, African Americans had significantly (p<0.0001) higher median levels of the two phenanthrene metabolites 3-hydroxyphenanthrene (3-PheOH, 0.931 pmol/ml) and phenanthrene tetraol (PheT, 1.13 pmol/ml) than Whites (3-PheOH, 0.697 pmol/ml; PheT, 0.853 pmol/ml) while Japanese-Americans had significantly (p = 0.002) lower levels of 3-PheOH (0.621 pmol/ml) than Whites. PheT levels (0.838 pmol/ml) in Japanese-Americans were not different from those of Whites. These results are mainly consistent with the lung cancer risk of these three groups, but the results for Native Hawaiians and Latinos were more complex. We also carried out a genome wide association study in search of factors that could influence PheT and 3-PheOH levels. Deletion of GSTT1 explained 2.2% of the variability in PheT, while the strongest association, rs5751777 (p = 1.8x10-62) in the GSTT2 gene, explained 7.7% of the variability in PheT. These GWAS results suggested a possible protective effect of lower GSTT1 copy number variants on the diol epoxide pathway, which was an unexpected result. Collectively, the results of this study provide further evidence that different patterns of cigarette smoking are responsible for the higher lung cancer risk of African Americans than of Whites and the lower lung cancer risk of Japanese Americans, while other factors appear to be involved in the differing risks of Native Hawaiians and Latinos.

Research from the Multiethnic Cohort (MEC) demonstrated that, for the same quantity of cigarette smoking, African Americans and Native Hawaiians have a higher lung cancer risk than Whites, while Latinos and Japanese Americans are less susceptible. We collected urine samples from 2,239 cigarette smokers from five different ethnic groups in the MEC and analyzed each sample for S-phenylmercapturic acid (SPMA), a specific biomarker of benzene uptake. African Americans had significantly higher (geometric mean [SE] 3.69 [0.2], p<0.005) SPMA/ml urine than Whites (2.67 [0.13]) while Japanese Americans had significantly lower levels than Whites (1.65 [0.07], p<0.005). SPMA levels in Native Hawaiians and Latinos were not significantly different from those of Whites. We also conducted a genome-wide association study in search of genetic risk factors related to benzene exposure. The glutathione S-transferase T1 (GSTT1) deletion explained between 14.2-31.6% (p = 5.4x10-157) and the GSTM1 deletion explained between 0.2%-2.4% of the variance (p = 1.1x10-9) of SPMA levels in these populations. Ethnic differences in levels of SPMA remained strong even after controlling for the effects of these two deletions. These results demonstrate the powerful effect of GSTT1 status on SPMA levels in urine and show that uptake of benzene in African American, White, and Japanese American cigarette smokers is consistent with their lung cancer risk in the MEC. While benzene is not generally considered a cause of lung cancer, its metabolite SPMA could be a biomarker for other volatile lung carcinogens in cigarette smoke.

Genetic variation in cytochrome P450 2A6 (CYP2A6) gene is the primary contributor to the intraindividual and interindividual differences in nicotine metabolism and has been found to influence smoking intensity. However, no study has evaluated the relationship between CYP2A6 genetic variants and the CYP2A6 activity ratio (total 3-hydroxycotinine/cotinine) and their influence on smoking intensity [total nicotine equivalents (TNE)], across five racial/ethnic groups found to have disparate rates of lung cancer. This study genotyped 10 known functional CYP2A6 genetic or copy number variants in 2115 current smokers from the multiethnic cohort study [African Americans (AA) = 350, Native Hawaiians (NH) = 288, Whites = 413, Latinos (LA) = 437 and Japanese Americans (JA) = 627] to conduct such an investigation. Here, we found that LA had the highest CYP2A6 activity followed by Whites, AA, NH and JA, who had the lowest levels. Adjusting for age, sex, race/ethnicity and body mass index, we found that CYP2A6 diplotypes were predictive of TNE levels, particularly in AA and JA (P trend < 0.0001). However, only in JA did the association remain after accounting for cigarettes per day. Also, it is only in this population that the lower activity ratio supports lower TNE levels, carcinogen exposure and thereby lower risk of lung cancer. Despite the association between nicotine metabolism (CYP2A6 activity phenotype and diplotypes) and smoking intensity (TNE), CYP2A6 levels did not correlate with the higher TNE levels found in AA nor the lower TNE levels found in LA, suggesting that other factors may influence smoking dose in these populations. Therefore, further study in these populations is recommended., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We prospectively examined the association between smoking and the risk of breast cancer in a racially/ethnically diverse population comprising mainly women who did not drink alcohol. From 1993 to 2010, we followed 83,300 women who were enrolled in the Multiethnic Cohort Study at 45-75 years of age. We identified cancer cases via linkage to the Surveillance, Epidemiology, and End Results Program cancer registries that covered the states of Hawaii and California through December 2010. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals while adjusting for confounders that were decided a priori. During a mean follow-up of 15 years, 4,484 women developed invasive breast cancer. Compared with parous never smokers, women who had smoked for more than 20 pack-years and initiated smoking more than 5 years before their first childbirth had an overall risk of breast cancer that was 35% higher (hazard ratio = 1.35, 95% confidence interval: 1.13, 1.63). Among women who did not drink alcohol, the risk was 40% higher (hazard ratio = 1.40, 95% confidence interval: 1.08, 1.81). This higher risk did not significantly differ among racial/ethnic groups (P(interaction) = 0.82). We found that various measures of smoking exposure were associated with a higher risk of breast cancer, especially smoking initiated many years before first childbirth, and that risk did not differ by alcohol consumption (yes vs. no) or racial/ethnic group., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Multiethnic Cohort epidemiology study has clearly demonstrated that, compared to Whites and for the same number of cigarettes smoked, African Americans and Native Hawaiians have a higher risk for lung cancer whereas Latinos and Japanese Americans have a lower risk. Acrolein and crotonaldehyde are two important constituents of cigarette smoke which have well documented toxic effects and could play a role in lung cancer etiology. Their urinary metabolites 3-hydroxypropylmercapturic acid (3-HPMA) and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), respectively, are validated biomarkers of acrolein and crotonaldehyde exposure. We quantified levels of 3-HPMA and HMPMA in the urine of more than 2200 smokers from these five ethnic groups, and also carried out a genome wide association study using blood samples from these subjects. After adjusting for age, sex, creatinine, and total nicotine equivalents, geometric mean levels of 3-HPMA and HMPMA were significantly different in the five groups (P < 0.0001). Native Hawaiians had the highest and Latinos the lowest geometric mean levels of both 3-HPMA and HMPMA. Levels of 3-HPMA and HMPMA were 3787 and 2759 pmol/ml urine, respectively, in Native Hawaiians and 1720 and 2210 pmol/ml urine in Latinos. These results suggest that acrolein and crotonaldehyde may be involved in lung cancer etiology, and that their divergent levels may partially explain the differing risks of Native Hawaiian and Latino smokers. No strong signals were associated with 3-HPMA in the genome wide association study, suggesting that formation of the glutathione conjugate of acrolein is mainly non-enzymatic, while the top significant association with HMPMA was located on chromosome 12 near the TBX3 gene, but its relationship to HMPMA excretion is not clear.

Background: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis., Methods: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided., Results: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5))., Conclusion: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Results of the Multiethnic Cohort (MEC) study demonstrated that, for the same quantity of cigarettes smoked, African Americans and Native Hawaiians have a higher risk of lung cancer compared with whites, whereas Latinos and Japanese Americans have a lower risk. We hypothesize that the uptake and/or metabolism of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) could explain the differences in lung cancer risk., Methods: We measured urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides and their sum (total NNAL), biomarkers of NNK uptake, in 2,252 smokers from the MEC. Ethnic-specific geometric means were compared adjusting for age at urine collection, sex, creatinine and total nicotine equivalents, a marker of total nicotine uptake., Results: African Americans had the highest median total NNAL levels (1.80 pmol/mL urine) and Japanese Americans had the lowest (0.914 pmol/mL urine), with intermediate values in the other three groups. Geometric mean of total NNAL in African Americans was also highest, and in Japanese Americans it was lowest; Japanese American geometric mean was statistically different from whites (P = 0.004)., Conclusions: African Americans had higher levels of total NNAL per mL urine than whites, while Japanese Americans had lower levels, consistent with lung cancer risk among smokers in these groups. However, our data were not consistent with the high and low lung cancer risks of Native Hawaiian and Latino smokers, respectively., Impact: The higher lung cancer susceptibility of African-American smokers and the lower susceptibility of Japanese-American smokers compared with whites can be explained in part by exposure to the potent lung carcinogen NNK. Cancer Epidemiol Biomarkers Prev; 24(3); 561-9. ©2014 AACR., (©2014 American Association for Cancer Research.)

Background: The lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these differences, as disparities in risk may be related to differences in nicotine dose and metabolism., Methods: We conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans, and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined., Results: Among 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (P < 5×10(-8)). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (P = 1.60 × 10(-155)). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explains 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, P = 2.56 × 10(-43)) was in high LD (r(2) = 0.99) with rs115765562., Conclusions: Genetic variation in UGT2B10 contributes significantly to nicotine and cotinine glucuronidation but not to nicotine dose., Impact: The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk., (©2014 American Association for Cancer Research.)

Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P < 0.0001), and N-glucuronidation lowest in AA (P < 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Smoking has recently been established as a risk factor for rectal cancer. We examined whether the smoking-related increase in rectal cancer differed by gender., Methods: We followed 602,242 participants (49% men), aged 19 to 67 years at enrollment from four Norwegian health surveys carried out between 1972 and 2003, by linkage to Norwegian national registries through December 2007. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by fitting Cox proportional hazard models and adjusting for relevant confounders. Heterogeneity by gender in the effect of smoking and risk of rectal cancer was tested with Wald χ2., Results: During a mean follow-up of 14 years, 1,336 men and 840 women developed invasive rectal cancer. Ever smokers had a significantly increased risk of rectal cancer of more than 25% for both men (HR = 1.27, 95% CI = 1.11-1.45) and women (HR = 1.28, 95% CI = 1.11-1.48) compared with gender-specific never smokers. Men smoking ≥20 pack-years had a significantly increased risk of rectal cancer of 35% (HR = 1.35, 95% CI = 1.14-1.58), whereas for women, it was 47% (HR = 1.47, 95% CI = 1.13-1.91) compared with gender-specific never smokers. For both men and women, we observed significant dose-response associations between the risk of rectal cancer for four variables [Age at smoking initiation in years (both ptrend <0.05), number of cigarettes smoked per day (both ptrend <0.0001), smoking duration in years (ptrend <0.05, <0.0001) and number of pack-years smoked (both ptrend <0.0001)]. The test for heterogeneity by gender was not significant between smoking status and the risk of rectal cancer (Wald χ2, p -value; current smokers = 0.85; former smokers = 0.87; ever smokers = 1.00)., Conclusions: Smoking increases the risk of rectal cancer to the same extent in women as in men.

Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.

Background: Smoking is a recently established risk factor for colon cancer. We wanted to explore the hypothesis that women may be more susceptible to smoking-attributed colon cancer than men as one of the possible explanations for the high colon cancer risk of Norwegian women., Methods: We followed 602,242 participants aged 19 to 67 years at enrollment in 1972-2003, by linkage to national registries through December 2007. We used Cox proportional hazard models to estimate HRs and 95% confidence intervals (CI)., Results: During a mean follow-up of 14 years, altogether 3,998 (46% women) subjects developed colon cancer. Female ever-smokers had a 19% (HR = 1.19, 95% CI = 1.09-1.32) and male ever-smokers an 8% (HR = 1.08, CI = 0.97-1.19) increased risk of colon cancer compared with never smokers. For all the four dose-response variables examined, female ever-smokers in the most exposed category of smoking initiation, (HR = 1.48, 95% CI = 1.21-1.81), of daily cigarette consumption (HR = 1.28, 95% CI = 1.06-1.55), of smoking duration (HR = 1.47, 95% CI = 1.11-1.95), and of pack-years of smoking (HR = 1.33, 95% CI = 1.11-1.57) had a significantly increased risk of more than 20% for colon cancer overall and of more than 40% for proximal colon cancer, compared with never smokers. A test for heterogeneity by gender was statistically significant only for ever smoking and risk of proximal colon cancer (Wald χ(2), P = 0.02)., Conclusions: Female smokers may be more susceptible to colon cancer and especially to proximal colon cancer than male smokers., Impact: Women who smoke are more vulnerable to colon cancer than men.

Objective: Heterocyclic amines (HAA) are animal carcinogens that are present in meat cooked at high temperature and in tobacco smoke. These compounds require activation by cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) before they can damage DNA. This study tested the hypotheses that well-done meat and cigarette smoking increase the risk of adenoma, the precursor to most colorectal cancers, especially in individuals with rapid CYP1A2 and rapid NAT2 activities., Design: An endoscopy-based case-control study of adenoma was conducted among Caucasians, Japanese and native Hawaiians to test this hypothesis. The overall diet and consumption of well-done meat cooked by various high-temperature methods were assessed by interview in 1016 patients with a first adenoma and 1355 controls with a normal endoscopy. A caffeine test was used to assess CYP1A2 and NAT2 activities in 635 cases and 845 controls. Logistic regression was used to account for matching factors and potential confounders., Results: Smoking was associated with an increased risk of adenoma. Weak non-significant elevated OR were observed for the main effects of HAA intakes or NAT2 activity. However, the combined effects of HAA intakes and NAT2 activity were statistically significant. Subjects in both the upper tertiles of NAT2 activity and HAA intake were at increased risk of adenoma compared with subjects in the lower tertiles of NAT2 activity and exposure (2-amino-3,4,8-dimethylimidazo[4,5-f]quinoxaline intake OR 1.70, 95% CI I 1.06 to 2.75; 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline intake OR 1.91, 95% CI 1.16 to 3.16; and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine intake OR 2.14, 95% CI 1.31 to 3.49)., Conclusion: The data suggest that rapid N-acetylators with high HAA intake may be at increased risk of adenoma.

Background: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored., Methods: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses., Results: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08)., Conclusions: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results., Clinical Trial Registration: NCT00000611.

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

Common polymorphisms in the N-acetyltransferase 2 gene (NAT2) modify the association between cigarette smoking and bladder cancer and have been hypothesized to determine whether active cigarette smoking increases breast cancer risk. The authors sought to replicate the latter hypothesis in a prospective analysis of 6,900 breast cancer cases and 9,903 matched controls drawn from 6 cohorts (1989-2006) in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. Standardized methods were used to genotype the 3 most common polymorphisms that define NAT2 acetylation phenotype (rs1799930, rs1799931, and rs1801280). In unconditional logistic regression analyses, breast cancer risk was higher in women with more than 20 pack-years of active cigarette smoking than in never smokers (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17, 1.39), after controlling for established risk factors other than alcohol consumption and physical inactivity. However, associations were similar for the slow (OR = 1.25, 95% CI: 1.11, 1.39) and rapid/intermediate (OR = 1.24, 95% CI: 1.08, 1.42) acetylation phenotypes, with no evidence of interaction (P = 0.87). These results provide some support for the hypothesis that long-term cigarette smoking may be causally associated with breast cancer risk but underscore the need for caution when interpreting sparse data on gene-environment interactions.

Background: The International Lung Cancer Consortium (ILCCO) was established in 2004, based on the collaboration of research groups leading large molecular epidemiology studies of lung cancer that are ongoing or have been recently completed. This framework offered the opportunity to investigate the role of tobacco smoking in the development of bronchioloalveolar carcinoma (BAC), a rare form of lung cancer., Methods: Our pooled data comprised seven case-control studies from the United States, with detailed information on tobacco smoking and histology, which contributed 799 cases of BAC and 15,859 controls. We estimated the odds ratio of BAC for tobacco smoking, using never smokers as a referent category, after adjustment for age, sex, race, and study center., Results: The odds ratio of BAC for ever smoking was 2.47 (95% confidence interval [CI] 2.08, 2.93); the risk increased linearly with duration, amount, and cumulative cigarette smoking and persisted long after smoking cessation. The proportion of BAC cases attributable to smoking was 0.47 (95% CI 0.39, 0.54)., Conclusions: This analysis provides a precise estimate of the risk of BAC for tobacco smoking.

Background: Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies., Methods: Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided., Results: Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer., Conclusions: In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

Native Hawaiian smokers are at higher risk and Japanese-American smokers at lower risk of lung cancer (LC), compared with white smokers, even after accounting for smoking history. Because variation in carcinogen exposure/metabolism may occur separately of smoking amount, we compared urinary biomarkers of uptake and detoxification of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-a potent lung carcinogen-among 578 smokers in these ethnic/racial groups in Hawaii. We measured the NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc) and examined total NNAL (NNAL + NNAL-Gluc) and the NNAL detoxification ratio (NNAL-Gluc:NNAL). Native Hawaiians and Japanese-Americans had lower age- and sex-adjusted mean total NNAL, compared with whites. When further adjusting for urinary nicotine equivalents (the sum of nicotine, cotinine, trans-3'-hydroxycotinine and their respective glucuronides), only the difference between Japanese-Americans and whites was eliminated. Therefore, consistent with their lower LC risk, a lower cigarette smoke exposure explains the lower NNK dose of Japanese-Americans, but it does not explain that of Native Hawaiians. The mean detoxification ratio was also lower in Native Hawaiians and Japanese-Americans, compared with whites, even after adjusting for nicotine equivalents (p < 0.0001). Lower NNAL glucuronidation in Native Hawaiians might contribute to their increased LC risk; however, this is inconsistent with the low glucuronidation ratio similarly observed in the low-risk Japanese-American group and because Native Hawaiians had lower total NNAL levels. Thus, exposure and detoxification of NNK are unlikely to explain, by themselves, the differences in LC risk among the 3 populations studied.

Introduction: Both smoking and alcohol consumption have been associated with modestly increased risks of colorectal cancer (CRC). Reports have suggested that these associations may differ by tumor molecular subtype, with stronger associations for microsatellite unstable (MSI-H) tumors., Methods: We used a population-based case-unaffected sibling design including 2,248 sibships (2,253 cases; 4,486 siblings) recruited to the Colon Cancer Family Registry to evaluate the association between smoking, alcohol consumption, and CRC. Associations were assessed using conditional logistic regression, treating sibship as the matching factor., Results: Although there were no statistically significant associations between any smoking variable and CRC overall, smoking did confer an increased risk of certain types of CRC. We observed an association between pack-years of smoking and rectal cancer [odds ratio (OR), 1.85; 95% confidence interval (CI), 1.23-2.79 for >40 pack-years versus nonsmokers; P(trend) = 0.03], and there was an increased risk of MSI-H CRC with increasing duration of smoking (OR, 1.94; 95% CI, 1.09-3.46 for >30 years of smoking versus nonsmokers). Alcohol intake was associated with a modest increase in risk for CRC overall (OR, 1.21; 95% CI, 1.03-1.44 for 12+ drinks per week versus nondrinkers), with more marked increases in risk for MSI-L CRC (OR, 1.85; 95% CI, 1.06-3.24) and rectal cancer (OR, 1.48; 95% CI, 1.08-2.02)., Conclusions: We found associations between cigarette smoking and increased risks of rectal cancer and MSI-H CRC. Alcohol intake was associated with increased risks of rectal cancer and MSI-L CRC. These results highlight the importance of considering tumor phenotype in studies of risk factors for CRC.

Objective: The association between cigarette smoking and colorectal cancer (CRC) is still not established. In 2002, Norwegian women had the second highest incidence of CRC in the world. A large proportion of Norwegian women are ever smokers. We examined the association between cigarette smoking and CRC incidence among Norwegian women., Methods: We followed 68,160 women, aged 30-69 years, from the Norwegian Women and Cancer Study who completed a questionnaire in 1996 or 1998 by linkages to national registers through 31 December 2005. Rate ratios (RRs) and 95% confidence intervals (CIs) were estimated by fitting Cox proportional hazard models. Subsequently, we estimated the population attributable fraction., Results: Altogether, 425 incident cases of primary, invasive CRC were identified. Ever smokers had a 20% increased risk of CRC (RR = 1.2; 95% CI = 1.0-1.5), a 30% increased risk of colon (RR = 1.3; 95% CI = 1.0-1.7), and a 10% increased risk of rectal (RR = 1.1; 95% CI = 0.7-1.5) cancer compared to never smokers. The population attributable fraction was estimated to be 12% which indicated that approximately one in eight of the CRC cases could have been prevented at a population level., Conclusion: Our results support the hypothesis that cigarette smoking is a preventable cause of CRC among women.

Background: N-acetyltransferases (NAT) 1 and 2 are polymorphic enzymes catalyzing the metabolic activation of heterocyclic amines. We investigated the modifying effects of NAT1 and NAT2 polymorphisms on the association of meat consumption, heterocyclic amine intake, and smoking with colorectal cancer risk., Method: In the Multiethnic Cohort study, participants completed a smoking history and a food-frequency questionnaire at recruitment and a cooked meat module 5 years later to estimate heterocyclic amine intake (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline). Blood samples were collected from incident cases and age-, sex-, ethnicity-, frequency-matched controls to determine genotypes. For analysis of meat intake and smoking, data were available for 1,009 cases and 1,522 controls; for heterocyclic amine intake analyses, 398 cases and 1,444 controls were available. Multivariate logistic regression models were used to estimate odds ratios., Results: Smoking was associated with an increased colorectal cancer risk (odds ratio, 1.51; 95% confidence interval, 1.17-1.95) for > or =30 pack-years compared with never smokers (P trend = 0.0004). The association was stronger with presence of the "rapid" compared with the "slow/intermediate" NAT2 genotype (P interaction = 0.003). No significant associations were observed for intakes of red meat, processed meat, and heterocyclic amine, or meat doneness preference, but a dietary pattern high in meat showed a weak positive interaction with the NAT2 genotype (P interaction = 0.05)., Conclusion: The enhanced association between smoking and colorectal cancer risk in subjects with the NAT2 rapid genotype supports a role for NAT2 and tobacco smoke heterocyclic amines in the etiology of colorectal cancer. This study only provides weak support for a similar association with meat heterocyclic amines.

Previously, we documented that smoking-associated lung cancer risk is greater in Hawaiians and lower in Japanese compared with Whites. Nicotine metabolism by cytochrome P450 2A6 (CYP2A6) varies across ethnicity/race and is hypothesized to affect smoking behavior. We investigated whether higher CYP2A6 activity results in the smoker extracting more nicotine (adjusting for cigarettes per day) and being exposed to higher levels of tobacco-specific nitrosamine [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)] and pyrene, a representative polycyclic aromatic hydrocarbon. We conducted a cross-sectional study of 585 smokers among the three main ethnic/racial groups in Hawaii and examined whether differences in CYP2A6 activity correlate with the ethnic/racial differences in lung cancer risk. We assessed CYP2A6 activity by nicotine metabolite ratio (total trans-3-hydroxycotinine/total cotinine) and caffeine metabolite ratio (1,7-dimethyl uric acid/1,7-dimethylxanthine) in 12 h urine. We also measured urinary nicotine equivalents (sum of nicotine, cotinine, and trans-3-hydroxycotinine and their respective glucuronides), a marker of nicotine dose, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide, markers of NNK exposure, and 1-hydroxypyrene, a marker of pyrene exposure. The nicotine metabolite ratio was higher in Whites than in Japanese and intermediate in Hawaiians (P values < 0.05). Cigarettes per day-adjusted nicotine equivalents were lower in Japanese compared with Hawaiians or Whites (P = 0.005 and P < 0.0001, respectively) and greater in men than women (P < 0.0001). Nicotine equivalents and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol increased with CYP2A6 activity, indicating that smokers with greater nicotine metabolism smoke more extensively and have a higher internal NNK dose. The particularly low nicotine metabolism of Japanese smokers may contribute to their previously described decreased lung cancer risk.

A locus at 15q24/15q25.1, which includes the nicotinic acetylcholine receptor A subunits 3 and 5 (CHRNA3 and CHRNA5) genes, has recently been associated with lung cancer risk, self-reported number of cigarettes smoked per day, and a nicotine dependence scale. It is not clear whether the association with lung cancer is direct or mediated through differences in smoking behavior. We used urinary biomarkers to test whether two linked lung cancer risk variants in CHRNA3 (rs1051730) and CHRNA5 (rs16969968) are associated with intensity of smoking and exposure to a tobacco-specific carcinogenic nitrosamine per cigarette dose. We studied 819 smokers and found that carriers of these variants extract a greater amount of nicotine (P = 0.003) and are exposed to a higher internal dose of 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (P = 0.03) per cigarette than noncarriers. Thus, smokers who carry the CHRNA3 and CHRNA5 variants are expected to be at increased risk for lung cancer compared with smokers who do not carry these alleles even if they smoked the same number of cigarettes. Number of cigarettes per day, even if it could be accurately assessed, is not an adequate measure of smoking dose.

To evaluate the roles of CYP1A1 polymorphisms [Ile 462Val and T 6235C (MspI)] and deletion of GSTM1 and GSTT1 in lung cancer development in Asian populations, a pooled analysis was conducted on 13 existing studies included in Genetic Susceptibility to Environmental Carcinogenesis database. This pooled analysis included 1,971 cases and 2,130 controls. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional logistic regression model adjusting for age, sex, and pack-year. The CYP1A1 6235C variant was associated with squamous cell lung cancer (TC versus TT: OR, 1.42; 95% CI, 0.96-2.09; CC versus TT: OR, 1.97; 95% CI, 1.26-3.07; P trend = 0.003). In haplotype analysis, 462Val-6235T and Ile-C haplotypes were associated with lung cancer risk with reference to the Ile-T haplotype (OR, 3.41; 95% CI, 1.78-6.53 and OR, 1.39; 95% CI, 1.12-1.71, respectively). The GSTM1-null genotype increased squamous cell lung cancer risk (OR, 1.36; 95% CI, 1.05-1.77). When the interaction was evaluated with smoking, increasing trend of lung cancer risk as pack-year increased was stronger among those with the CYP1A1 6235 TC/CC genotype compared with those with TT genotype (P interaction = 0.001) and with the GSTM1-null genotype compared with the present type (Pinteraction = 0.08, when no genotype effect with no exposure was assumed). These results suggest that genetic polymorphisms in CYP1A1 and GSTM1 are associated with lung cancer risk in Asian populations. However, further investigation is warranted considering the relatively small sample size when subgroup analyses were done and the lack of environmental exposure data other than smoking.

Although smoking is suggested to be a risk factor for colorectal cancer, the evidence to date is conflicting and may be confounded. Moreover, the effect of tobacco smoke may vary by time since initiation, type of tobacco product, anatomic subsites, and among ethnic groups. Data were derived from two consecutive population-based case-control studies conducted among Caucasians, Japanese, Native Hawaiians, Filipinos, and Chinese in Hawaii, including 1,959 ethnicity-, sex-, and age-matched case-control pairs. A lifetime history of smoking for different tobacco products and information on other risk factors were obtained by in-person interviews. Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were estimated using conditional logistic regression models with adjustment for potential confounders. Subjects who ever smoked were at an increased risk of colorectal cancer compared with never smokers (OR, 1.23; 95% CI, 0.99-1.52 for men and OR, 1.27; 95% CI, 1.01-1.59 for women). Increasing quartiles of pack-years over all tobacco products showed a clear dose-dependent association in men [for the highest quartile, Q4 (>40 pack-years) versus never smokers: OR, 1.48; 95% CI, 1.12-1.96; P(trend) = 0.002]. The dose-response trend was also present in women [for the highest quartile, Q4 (>30 pack-years) versus never smokers: OR, 1.38; 95% CI, 0.91-1.95; P(trend) = 0.04] and each ethnic group. There was a suggestion of a difference in risk with type of tobacco product. Non-filtered cigarettes increased risk of both colon and rectal cancer [for Q4 versus never smokers: OR, 1.59; 95% CI, 1.15-2.21; P(trend) = 0.001 and OR, 1.84; 95% CI, 1.18-2.86; P(trend) = 0.02, respectively], whereas filtered cigarettes seemed to increase risk of rectal but not colon cancer (OR, 1.37; 95% CI, 0.88-2.13; P(trend) = 0.06 and OR, 1.05; 95% CI, 0.79-1.39; P(trend) = 0.98, respectively). The effect of smoking was not limited to the distant past, and accumulated pack-years of smoking seemed to be more important than the time in which smoking occurred. The data from this large study corroborate previous reports of a positive association between smoking and colorectal cancer and suggest that the association may vary by type of cigarette.

Background: There is remarkable variation in the incidence of lung cancer among ethnic and racial groups in the United States., Methods: We investigated differences in the risk of lung cancer associated with cigarette smoking among 183,813 African-American, Japanese-American, Latino, Native Hawaiian, and white men and women in the Multiethnic Cohort Study. Our analysis included 1979 cases of incident lung cancer identified prospectively over an eight-year period, between baseline (1993 through 1996) and 2001., Results: The risk of lung cancer among ethnic and racial groups was modified by the number of cigarettes smoked per day. Among participants who smoked no more than 30 cigarettes per day, African Americans and Native Hawaiians had significantly greater risks of lung cancer than did the other groups. Among those who smoked no more than 10 and those who smoked 11 to 20 cigarettes per day, relative risks ranged from 0.21 to 0.39 (P<0.001) among Japanese Americans and Latinos and from 0.45 to 0.57 (P<0.001) among whites, as compared with African Americans. However, at levels exceeding 30 cigarettes per day, these differences were not significant. Differences in risk associated with smoking were observed among both men and women and for all histologic types of lung cancer., Conclusions: Among cigarette smokers, African Americans and Native Hawaiians are more susceptible to lung cancer than whites, Japanese Americans, and Latinos., (Copyright 2006 Massachusetts Medical Society.)

Background: The prevalence of smoking continues to be higher in some ethnic groups than in others, despite the overall decrease of smoking during the last 30 years. The goal of this project was to investigate the trends and predictors of cigarette smoking among a population of Caucasians, Japanese, Chinese, Filipino, and Native Hawaiians., Methods: We combined data from 19 earlier studies conducted in Hawaii between 1975 and 2001. After excluding 1,885 individuals without smoking data, 158,629 subjects (40.0% Japanese, 30.3% Caucasian, 14.3% Hawaiian, 8.1% Filipino, 3.0% Chinese) were included in the analysis. The prevalence of current smoking and past smoking was estimated for 5-year periods by sex and ethnicity and age-adjusted to the state's population. We calculated odds ratios and 95% confidence intervals by using polytomous logistic regression to explore determinants of smoking, while controlling for clustering by study., Results: Men were more likely to smoke than women throughout the study period, but they experienced a greater decline in smoking until 1994. We observed a small increase in smoking prevalence thereafter. Native Hawaiians reported the highest smoking prevalence, Japanese the lowest, and Caucasians intermediate levels. Graduate level education had the strongest inverse association with current and past smoking. Older age at interview, being married, and a higher body weight were related to lower smoking prevalence., Conclusions: Our data suggest a modest reversal in the declining smoking prevalence during the late 1990s. The persistent ethnic differences require new approaches that reach those groups who remain at high risk for adverse health effects from smoking.

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected., (Copyright 2004 Wiley-Liss, Inc.)

Polymorphisms for genes encoding the metabolic enzymes cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) might contribute to the variability in individual susceptibility to lung cancer. The role of CYP1A1 and GSTM1 in lung carcinogenesis might be more important at low levels of exposure to carcinogens. Non-smokers represent a population at low exposure, however, they are often overlooked because of the small number of cases. We therefore conducted a pooled analysis of 14 case-control studies on lung cancer in Caucasian non-smokers with comparable information on genetic polymorphisms included in the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens. We pooled the raw data from a total of 302 cases and 1631 controls with random effects models. We also evaluated the possibility of inclusion bias and conducted influence analyses. The odds ratio (OR) of lung cancer for the variant CYP1A1 Ile(462)Val polymorphism (Ile/Val, Val/Val) was 2.99 [95% confidence interval (95%CI) 1.51-5.91]; this effect was stronger on lung adenocarcinoma (OR 4.85, 95%CI 2.03-11.6). After excluding outlying or imprecise studies, we did not observe a significant effect of the CYP1A1 MspI (T(3801)C) polymorphism or GSTM1 null genotype (OR 1.20, 95%CI 0.89-1.63). Furthermore, our analyses suggested a combined effect of the CYP1A1 Ile(462)Val polymorphism and GSTM1 null genotype. The OR for the combination of the CYP1A1 Ile(462)Val variant and GSTM1 null genotype was 4.67 (95%CI 2.00-10.9) compared with the concurrent presence of the CYP1A1 wild-type and GSTM1 non-null genotype. We did not observe a modification of the effect of the GSTM1 null genotype according to exposure to environmental tobacco smoke and urban/rural residence. Our study therefore suggests that the CYP1A1 Ile(462)Val variant allele might play a role in lung carcinogenesis among non-smokers, possibly in combination with the GSTM1 null genotype.