Increased Risk Of Lung Cancer Research Articles

Polymorphisms in DNA Repair and Xenobiotic Biotransformation Enzyme Genes and Lung Cancer Risk in Coal Mine Workers.

Background: Currently coal mining employs over 7 million miners globally. This occupational setting is associated with exposure to dust particles, heavy metals, polycyclic aromatic hydrocarbons and radioactive radon, significantly increasing the risk of lung cancer (LC). The susceptibility for LC is modified by genetic variations in xenobiotic detoxification and DNA repair capacity. The aim of this study was to investigate the association between GSTM1 (deletion), APEX1 (rs1130409), XPD (rs13181) and NBS1 (rs1805794) gene polymorphisms and LC risk in patients who worked in coal mines. Methods: The study included 639 residents of the coal region of Western Siberia (Kemerovo region, Russia): 395 underground miners and 244 healthy men who do not work in industrial enterprises. Genotyping was performed using real-time and allele-specific PCR. Results: The results show that polymorphisms of APEX1 (recessive model: ORadj = 1.87; CI 95%: 1.01–3.48) and XPD (log additive model: ORadj = 2.25; CI 95%: 1.59–3.19) genes were associated with increased LC risk. GSTM1 large deletion l was linked with decreased risk of LC formation (ORadj = 0.59, CI 95%: 0.36–0.98). The multifactor dimensionality reduction method for 3-loci model of gene–gene interactions showed that the GSTM1 (large deletion)—APEX1 (rs1130409)—XPD (rs13181) model was related with a risk of LC development. Conclusions: The results of this study highlight an association between gene polymorphism combinations and LC risks in coal mine workers.

BMI changes and the risk of lung cancer in male never-smokers: A prospective cohort study.

BackgroundTo investigate the association between the risk of lung cancer and short‐term body mass index (BMI) changes in male never‐smokers of a large population‐based prospective study.MethodsA total of 37,085 male never‐smokers from Kailuan cohort with at least ≥2 BMI measurements were recruited in the present study. The BMI change in the follow‐up was calculated as the annual percent change between BMI at last examination and that at baseline, and categorized into five groups: stable (−0.1 to <0.1 kg/m2/year), minor loss (−1.0 to <0.1 kg/m2/year) or gain (0.1 to <1.0 kg/m2/year), and major loss (<−1.0 kg/m2/year) or gain (≥1.0 kg/m2/year). The hazards ratios (HRs) and its 95% confidence intervals (CI) were estimated using Cox regression models.ResultsDuring a median follow‐up of 5.16 years, 224 lung cancer cases were identified. We found a U‐shaped association between BMI changes and lung cancer risk. Compared to men with stable BMI, those with major loss had a nearly twofold higher risk of lung cancer (HR = 1.97, 95% CI: 1.12–3.45), as well as those with major gain had more than twofold higher risk of lung cancer (HR = 2.15, 95% CI: 1.15–4.02). The associations existed when the analysis was stratified by BMI, waist circumference and blood lipids, and lipoproteins concentration at baseline examination.ConclusionsThe dramatic changes in BMI, both gain and loss, might increase lung cancer risk. The control of body weight would be a potential way for lung cancer prevention especially for the nonsmokers.

Occupational Exposures and Lung Cancer Risk-An Analysis of the CARTaGENE Study.

To determine the associations between prevalent occupational agents and lung cancer risk. A case-cohort design (ncases= 147; nsub-cohort= 1,032) was nested within the CARTaGENE prospective cohort study. The Canadian Job Exposure Matrix was used to determine the probability of exposure to 27 agents in participants' longest-held jobs. Multivariable logistic regression with robust variance estimators was used to determine the associations between each agent and lung cancer risk while adjusting for established lung cancer risk factors. Increased lung cancer risk was observed among those exposed to ashes, calcium sulfate, formaldehyde, cooking fumes, alkanes, aliphatic aldehydes, and cleaning agents. Lower lung cancer risk was found among participants exposed to carbon monoxide and polycyclic aromatic hydrocarbons from petroleum. Our findings support the role of several occupational agents, for which we have limited knowledge, in contributing to lung cancer risk.

Real-world PM2.5 exposure induces pathological injury and DNA damage associated with miRNAs and DNA methylation alteration in rat lungs.

Fine particulate matter (PM2.5) has been demonstrated to threaten public health and increase lung cancer risk. DNA damage is involved in the pathogenesis of lung cancer. However, the mechanisms of epigenetic modification of lung DNA damage are still unclear. This study developed a real-world air PM2.5 inhalation system and exposed rats for 1 and 2 months, respectively, and investigated rat lungs pathological changes, inflammation, oxidative stress, and DNA damage effects. OGG1 and MTH1 expression was measured, along with their DNA methylation status and related miRNAs expression. The results showed that PM2.5 exposure led to pathological injury, influenced levels of inflammatory cytokines and oxidative stress factors in rat lungs. Of note, 2-month PM2.5 exposure aggravated pathological injury. Besides, PM2.5 significantly elevated OGG1 expression and suppressed MTH1 expression, which was correlated to oxidative stress and partially mediated by reducing OGG1 DNA methylation status and increasing miRNAs expression related to MTH1 in DNA damage with increases of γ-H2AX, 8-OHdG and GADD153. PM2.5 also activated c-fos and c-jun levels and inactivated PTEN levels in rat lungs. These suggested that epigenetic modification was probably a potential mechanism by which PM2.5-induced genotoxicity in rat lungs.

A Two-Stage Mendelian Randomization Analysis of Million-Scale Data Reveals Thyroid Dysfunction Casually Associated with Increased Lung Cancer Risk Among Smokers

A Two-Stage Mendelian Randomization Analysis of Million-Scale Data Reveals Thyroid Dysfunction Casually Associated with Increased Lung Cancer Risk Among Smokers

The First Attempt to Reevaluate Radon and Thoron Exposure in Gansu Province Study Using Radon-Thoron Discriminating Measurement Technique.

Although the epidemiological studies provide evidence for an increased risk of lung cancer risk associated with residential radon, an issue of radon-thoron discrimination remains to be solved. In this study, an updated evaluation of lung cancer risk among the residents in Gansu, China was performed where one of the major epidemiological studies on indoor radon demonstrated an increased risk of lung cancer. We analyzed data from a hospital-based case-control study that included 30 lung cancer cases and 39 controls with special attention to internal exposure assessment based on the discriminative measurement technique of radon isotopes. Results from the analyses showed non-significant increased lung cancer risks; odds ratios (ORs) adjusted for age, smoking, and total income were 0.35 (95% CI: 0.07–1.74) and 0.27 (95% CI: 0.04–1.74) for groups living in residences with indoor radon concentrations of 50–100 Bq m−3 and over 100 Bq m−3, respectively, compared with those with < 50 Bq m−3 indoor radon concentrations. Although the small sample size hampers the usefulness of present analyses, our study suggests that reevaluation of lung cancer risk associated with residential radon in the epidemiological studies will be required on the basis of precise exposure assessment.

Lung cancer risk following previous abnormal chest radiographs: A 27-year follow-up study of a Chinese lung screening cohort.

Background Chest radiograph (CXR) is still one of the most commonly used diagnostic tools for chest diseases. In this cohort study, we attempted to investigate the magnitude and temporal pattern of lung cancer risk following abnormal CXR findings.MethodsWe conducted an extended follow‐up of an occupational screening cohort in Yunnan, China. The associations between abnormal CXR results from baseline screening, the first four consecutive rounds of CXR screening, all previous rounds of screening and lung cancer risk were analyzed using time‐varying coefficient Cox regression model. The associations of lung cancer risk and previous CXR‐screening results according to histology were also considered. Sensitivity analyses were conducted to assess the robustness of the previous abnormal CXR findings on subsequent lung cancer risk.ResultsAbnormal CXR findings were associated with a significantly increased lung cancer risk. This relative hazard significantly decreased over time. Compared to negative screening results, the adjusted hazard ratios (HR) of baseline abnormal CXR results, and at least one abnormal result in the first four consecutive screening rounds during the first 5 years of follow‐up were 17.06 (95% CI: 11.74–24.79) and 13.77 (95%: 9.58–17.79), respectively. This significantly increased lung cancer risk continued over the next 5 years. These associations were stronger for persistent abnormal findings, and abnormal findings identified in recent screening rounds.ConclusionsThe increased risk was significant for both squamous cell carcinoma and adenocarcinoma. Although decreased over time, an increased lung cancer risk relative to abnormal CXR findings can continue for 10 years.

Menstrual factors, reproductive history, and risk of lung cancer: a multi-center population-based cohort study in Chinese females.

BackgroundFemale menstrual and reproductive factors, as remarkable indicators of hormone effect, were hypothesized to be associated with lung cancer risk, whereas the existed epidemiological evidence was inconsistent. Our study aims to investigate the association between menstrual and reproductive factors and lung cancer risk based on the Chinese Lung Cancer Screening Program.MethodsThis study was based on a large-scale multi-center population cohort across China recruiting individuals aged 40–74 years old between 2013–2018. Cox regression model was applied to estimate the HRs and 95% CIs. Restricted cubic spline (RCS) analysis was used to estimate dose-response relationships and test for nonlinear associations.ResultsAmong 553,434 female participants, 1,529 incident lung cancer cases were identified with a median follow-up of 3.61 years. With adjustment for multiple covariates and all significant hormonal factors, elevated lung cancer risk was associated with later age (15, or ≥16 years) at menarche (HR =1.27, 95% CI: 1.04–1.56; HR =1.45, 95% CI: 1.19–1.76), later age (25–29, or ≥30 years) at first live birth (HR =1.27, 95% CI: 1.13–1.43; HR =1.23, 95% CI: 1.00–1.51), and benign breast disease history (HR =1.25, 95% CI: 1.10-1.41). For postmenopausal females specifically, surgical menopause (HR =1.62; 95% CI: 1.29–2.05) and other surgeries on the reproductive system (HR =1.19; 95% CI: 1.01–1.40) both appeared to be predictive of elevated lung cancer risk. Concerning age at menopause, a nonlinear association was observed (P-nonlinear =0.0126). Increased lung cancer risk was observed among females with age at menopause especially above 50. Although we observed no significant associations between longer time (≥13 months) of breastfeeding and lung cancer risk among all participants (HR =0.86; 95% CI: 0.71–1.04), significant decreased adenocarcinoma risk (HR =0.65; 95% CI: 0.53–0.81) was noted among nonsmoking females.ConclusionsOur findings add some support for the role of menstrual and reproductive factors in lung carcinogenesis. However, these relationships were complex, and required further investigations addressing the biological mechanisms.

Circulating C-reactive protein increases lung cancer risk: Results from a prospective cohort of UK Biobank.

Chronic inflammation has been associated with the development of lung cancer. In this study, we examined the association between C-reactive protein (CRP) and lung cancer in a prospective cohort study and used Mendelian randomization (MR) to clarify the causality. We included 420 977 participants from the UK Biobank (UKB) in the analyses; 1892 thereof were diagnosed with lung cancer during the follow-up. Hazards ratios (HRs) of CRP concentrations were estimated by Cox proportional hazard models and two approaches of MR analysis were performed. Besides, we added CRP concentrations to epidemiological model of lung cancer to evaluate its prediagnostic role through time-dependent receiver operating characteristic curve analysis. Elevated CRP levels were associated with a 22% increased lung cancer risk per 1 SD increase (HR=1.22, 95% confidence interval [CI]=1.18-1.26). Positive associations were observed in small cell lung cancer (HR=1.21, 95%CI=1.10-1.33), lung adenocarcinoma (HR=1.17, 95%CI=1.11-1.23) and lung squamous cell carcinoma (HR=1.22, 95%CI=1.14-1.31). No genetical association of circulating CRP levels and lung cancer risk was observed in MR analysis. When added to a risk model of lung cancer, CRP improved the performance of model as long as 8 years among current smokers (basic model: C-statistic=0.78 [95%CI=0.75-0.80]; CRP model: C-statistic=0.79 [95%CI=0.76-0.81]; Pnonadjusted =.003, Padjusted =.014). Our results did not support the causal association of circulating CRP with lung cancer risk. However, circulating CRP could be a prediagnostic marker of lung cancer as long as 8 years in advance for current smokers.

956Cumulative low-tar exposure was still associated with increased lung cancer risk from Japanese case-control study

Abstract Background Tar concentration in cigarette brands is chronologically decreasing in the USA and Japan. However, studies investigating lung cancer risk with cumulative tar exposure in Western and Asian countries are insufficient. To investigate the risk of lung cancer with cumulative cigarette tar exposure, we conducted a case-control study among Japanese current smokers. Methods This study used data from the US-Japan lung cancer joint study in 1993–1998. The number of the subjects was 282 histologically confirmed lung cancer cases and 162 hospital and 227 community controls, and two control groups were combined. The information regarding tar concentration was obtained from the published documents and additional estimation using the equation of regression. Cumulative tar concentration was calculated by multiplying the annual value of tar concentration by year and brand. The odds ratios (ORs) and 95% confidence intervals for lung cancer with cumulative tar exposure were estimated using a logistic model. Results The OR with cumulative tar exposure was higher in higher exposed smokers (&amp;gt;45.6 × 105mg, 8.10, 4.74–13.7) than in lower exposed smokers (≤45.6 × 105mg, 3.37, 1.92–5.92), and increasing trend of the ORs was significant (p &amp;lt; 0.001). The stratification analysis showed higher ORs among those with higher cumulative tar exposure regardless of inhalation, duration of smoking filtered cigarettes, and histological type. Conclusions This study showed that cumulative tar exposure is a dose-dependent indicator for lung cancer risk, and low-tar exposure was still associated with increased cancer risk. Key messages Low-tar tobacco is still associated with increased lung cancer risk.

Associations of polycyclic aromatic hydrocarbons exposure and its interaction with XRCC1 genetic polymorphism with lung cancer: A case-control study

Humans are extensively exposed to polycyclic aromatic hydrocarbons (PAHs) daily via multiple pathways. Epidemiological studies have demonstrated that occupational exposure to PAHs increases the risk of lung cancer, but related studies in the general population are limited. Hence, we conducted a case-control study among the Chinese general population to investigate the associations between PAHs exposure and lung cancer risk and analyze the modifications of genetic polymorphisms in DNA repair genes. In this study, we enrolled 122 lung cancer cases and 244 healthy controls in Wuhan, China. Urinary PAHs metabolites were determined by gas chromatography-mass spectrometry, and rs25487 in X-ray repair cross-complementation 1 (XRCC1) gene was genotyped by the Agena Bioscience MassARRAY System. Then, multivariable logistic regression models were performed to estimate the potential associations. We found that urinary hydroxynaphthalene (OH-Nap), hydroxyphenanthrene (OH-Phe) and the sum of hydroxy PAHs (∑OH-PAHs) levels were significantly higher in lung cancer cases than those in controls. After adjusting for gender, age, BMI, smoking status, smoking pack-years, drinking status and family history, urinary ∑OH-Nap and ∑OH-Phe levels were positively associated with lung cancer risk, with dose-response relationships. Compared with those in the lowest tertiles, individuals in the highest tertiles of ∑OH-Nap and ∑OH-Phe had a 2.13-fold (95% CI: 1.10, 4.09) and 2.45-fold (95% CI: 1.23, 4.87) increased risk of lung cancer, respectively. Effects of gender, age, smoking status and smoking pack-years on the associations of PAHs exposure with lung cancer risk were shown in the subgroup analysis. Furthermore, associations of urinary ∑OH-Nap and ∑OH-PAHs levels with lung cancer risk were modified by XRCC1 rs25487 (Pinteraction ≤ 0.025), and were more pronounced in wild-types of rs25487. These findings suggest that environmental exposure to naphthalene and phenanthrene is associated with increased lung cancer risk, and polymorphism of XRCC1 rs25487 might modify the naphthalene exposure-related lung cancer effect.

Long-term Lung Cancer Risk Associated with Sputum Atypia: A 27-Year Follow-up Study of an Occupational Lung Screening Cohort in Yunnan, China.

Sputum cytologic atypia is associated with increased lung cancer risk. However, little is known about the long-term magnitude and temporal trend of this risk. An extended follow-up was conducted in a prospective screening cohort among occupational tin miners in Yunnan, China. Sputum samples were collected prospectively at baseline and 7 annual screenings since enrollment. The associations between sputum cytologic results from baseline screening, the first 4 consecutive rounds of sputum screening, and lung cancer risk were analyzed by time-varying covariate Cox regression model. A moderate or worse cytologic result was associated with a significantly increased lung cancer risk. This relative hazard significantly decreased over time. Compared with negative screening results, the adjusted hazard ratios of baseline-moderate or worse atypia, at least one moderate or worse atypia in the first 4 consecutive screening rounds during the first 10 years of follow-up were 3.11 [95% confidence interval (CI): 2.37-4.07], 3.25 (95% CI: 2.33-4.54) respectively. This association was stronger for persistent atypia (adjusted hazard ratio = 17.55, 95% CI: 8.32-37.03); atypia identified in the recent screening rounds (adjusted HR = 4.14, 95% CI: 2.70-6.35), and those were old in age, had higher level of smoking, occupational radon, and arsenic exposure. In terms of histology, this increased risk was significant for squamous cell carcinoma and small cell lung cancer. Although decreasing over time, an increased lung cancer risk concerning moderate or worse sputum atypia can continue at least for 10 years. Sputum atypia might be helpful for identifying high-risk individuals for screening, surveillance, or chemoprevention of lung cancer.

Association of CYP2C19*2/3 gene polymorphism with lung cancer in Moroccan population

BackgroundAs it is the case for all kinds of cancer; lung cancer is a multifactorial disease. The interaction between both Exposures to different carcinogens and individual genetic backgrounds modulate the disease risk. Cytochrome P450 family is one of the main enzymes involved in the metabolism of these carcinogens. Therefore, polymorphisms of genes encoding for the cyp450 enzymes can be responsible for the inter-individual differences in lung cancer susceptibility. In this study, we chose to focus on the Cyp2c19, as one of the crucial cyp450 enzymes associated with metabolism of a number of drugs and xenobiotics and its association with the lung cancer risk. MethodsPeripheral blood from a total of 115 Moroccan patients diagnosed with lung cancer and 105 healthy subjects was collected. The genotyping of CYP2C19*2 and CYP2C19*3 polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technic. ResultsWe found that the frequency of both CYP2C19*2 (GA+AA) genotype and CYP2C19*A allele were significantly more frequent in lung cancer patients than that in control subjects (24.3% vs 13.3%; p = 0.04 and 14.35% vs 7.15%; p = 0.01 respectively). We also found that the CYP2C19*3 A allele was only found in lung cancer patient with a frequency of 10% (p = 0.007). Consequently, the frequency of the CYP2C19*3 (GA + AA) genotype was also significantly more prevalent in lung cancer patients than that in controls (20% vs 0.00%; p = 0.005). We also found that smoking is associated to a higher lung cancer risk in participants carrying CYP2C19*3 or CYP2C19*2 GG genotypes (p < 0.0001, OR = 26.42, 95%CI = 12.38–56.36) and (p < 0.0001, OR = 24,44, 95%CI = 11,13–53,65). While the binary logistic regression analysis demonstrates that interaction of CYP2C19*2 with smoking has no effect on the lung cancer risk, unlike the CYP2C19*3 which coexisted with smoking increases lung cancer risk even more. ConclusionThese findings indicate that the CYP2C19*2 and CYP2C19*3 polymorphisms are significantly associated with lung cancer in Moroccan population. In addition, that the coexistence of CYP2C19*3 with smoking increased lung cancer risk even more.

Dual Nature of Relationship between Mycobacteria and Cancer.

Although the therapeutic effect of mycobacteria as antitumor agents has been known for decades, recent epidemiological and experimental studies have revealed that mycobacterium-related chronic inflammation may be a possible mechanism of cancer pathogenesis. Mycobacterium tuberculosis and non-tuberculous Mycobacterium avium complex infections have been implicated as potentially contributing to the etiology of lung cancer, whereas Mycobacterium ulcerans has been correlated with skin carcinogenesis. The risk of tumor development with chronic mycobacterial infections is thought to be a result of many host effector mechanisms acting at different stages of oncogenesis. In this paper, we focus on the nature of the relationship between mycobacteria and cancer, describing the clinical significance of mycobacteria-based cancer therapy as well as epidemiological evidence on the contribution of chronic mycobacterial infections to the increased lung cancer risk.

Abstract 848: Sleep behaviors and risk of lung cancer in the UK Biobank

Abstract Background. Lung cancer is the second most common malignancy and the leading causes of cancer death in both men and women in the United States. Cross-sectional studies on sleep disorders showed that sleep apnea and nocturnal hypoxemia are associated with an increased risk of lung cancer. Studies on sleep patterns are largely limited to sleep duration, snoring, insomnia and narcolepsy, in which short or long sleep duration, insomnia and narcolepsy are associated with an increased lung cancer risk. However, the association with other sleep patterns such as chronotype has not yet been investigated and the joint collective impact of sleep behaviors on lung cancer risk remains undetermined. In this study, we examined the association of six sleep behaviors with risk of lung cancer overall and among subgroups defined by smoking status and sex. Methods. A total of 410,252 UK Biobank participants free of lung cancer aged 37-73 years recruited in 2006-2010 were included. Lung cancer cases were identified from cancer registry or death records up to September 2020. Self-reported sleep behaviors (chronotype, duration, daytime nap, snoring, insomnia, and narcolepsy) were collected at study baseline. Multivariable Cox proportional hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CIs) for each sleep behavior and risk of lung cancer. A composite unhealthy sleep score (0-3) was further developed by summing the individual score of three unhealthy sleep behaviors: evening chronotype, sleep &amp;lt;7 or &amp;gt;8 h/day, and usual daytime nap, with higher scores indicating a higher-risk sleep pattern. Stratified analyses jointly by smoking status (never vs. ever) and sex were conducted. Results. During up to 13.6 years of follow up with 4,693,213 person-years, a total of 2,897 lung cancer cases were documented. Compared with individuals with morning chronotype, participants with evening chronotype had an 11% increased risk of lung cancer (HR: 1.11, 95%CI: 0.98-1.26). Those who slept &amp;lt;7 or &amp;gt;8 h/day had 9-25% increased risk compared with individuals who slept 7-8 hours. Compared with those who never took daytime nap, participants with usual nap had an 14% increased lung cancer risk (HR: 1.14, 95%CI: 1.00-1.30). Snoring, insomnia and narcolepsy were not associated with lung cancer risk. Compared with participants without any of high-risk sleep behavior (evening chronotype, sleep &amp;lt;7 or &amp;gt;8 h/day, and usual daytime nap), those with 1 high-risk behavior had 12% (HR: 1.12, 95%CI: 1.04-1.21) increased risk of lung cancer, and individuals with 2 or 3 high-risk sleep behaviors had a 30% (HR: 1.30, 95%CI: 1.15-1.47) increased risk of lung cancer (Ptrend &amp;lt; 0.001). Such association was similarly observed among male and female smokers, but was slightly stronger in male never smokers compared to females. Conclusion. Unhealthy sleep behaviors including evening chronotype, sleep &amp;lt;7 or &amp;gt;8 hours per day, and usual daytime nap was associated with increased risk of lung cancer. Citation Format: Xiaoyan Wang, Xiaoyu Zong, Na Li, Ramaswamy Govindan, Graham Colditz, Yin Cao. Sleep behaviors and risk of lung cancer in the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 848.

The Inverse Association of Body Mass Index with Lung Cancer: Exploring Residual Confounding, Metabolic Aberrations and Within-Person Variability in Smoking

Abstract Background: The inverse observational association between body mass index (BMI) and lung cancer risk remains unclear. We assessed whether the association is explained by metabolic aberrations, residual confounding, and within-person variability in smoking, and compared against other smoking-related cancers. Methods: We investigated the association between BMI, and its combination with a metabolic score (MS) of mid-blood pressure, glucose, and triglycerides, with lung cancer and other smoking-related cancers in 778,828 individuals. We used Cox regression, adjusted and corrected for within-person variability in smoking (status/pack-years), calculated from 600,201 measurements in 221,958 participants. Results: Over a median follow-up of 20 years, 20,242 smoking-related cancers (6,735 lung cancers) were recorded. Despite adjustment and correction for substantial within-person variability in smoking, BMI remained inversely associated with lung cancer [HR per standard deviation increase, 0.87 (95% confidence interval 0.85–0.89)]. Individuals with BMI less than 25 kg/m2 and high MS had the highest risk [HR 1.52 (1.44–1.60) vs. BMI ≥25 with low MS]. These associations were weaker and nonsignificant among nonsmokers. Similar associations were observed for head and neck cancers and esophageal squamous cell carcinoma, whereas for other smoking-related cancers, we generally observed positive associations with BMI. Conclusions: The increased lung cancer risk with low BMI and high MS is unlikely due to residual confounding and within-person variability in smoking. However, similar results for other cancers strongly related to smoking suggest a remaining, unknown, effect of smoking. Impact: Extensive smoking-adjustments may not capture all the effects of smoking on the relationship between obesity-related factors and risk of smoking-related cancers.

Commute patterns, residential traffic-related air pollution, and lung cancer risk in the prospective UK Biobank cohort study

IntroductionCommuting exposes millions of people to carcinogens from traffic-related air pollution (TRAP) but is seldomly considered in epidemiologic studies of lung cancer. In the prospective United Kingdom (UK) Biobank cohort study, we investigated associations between commute patterns, residential nitrogen dioxide concentrations (NO2; a surrogate for TRAP), and lung cancer risk. MethodsWe analyzed 234,124 employed participants at baseline (2006–2010). There were 493 incident lung cancer cases diagnosed over an average 7-year follow-up. Subjects were cross-classified into exclusive categories of commute mode (automobile, public transportation, walking, cycling, active mixture, and other mixture) and frequency (regular: 1–4, often: ≥5 work-bound trips/week). Annual average residential NO2 concentrations in 2005–2007 were estimated with land use regression. Multivariable Cox regression was used to estimate associations between commute patterns, NO2 quartiles, and incident lung cancer. We conducted analyses stratified by NO2 (>, ≤median = 28.3 µg/m3) and potential confounders such as sex and smoking. ResultsCompared to regular automobile use, commuting often by public transportation was associated with increased lung cancer risk (hazard ratio (HR) = 1.58, 95% confidence intervals (CI):1.08–2.33). Additionally, we found a positive exposure–response relationship with residential NO2 (HRQ2 = 1.21, 95 %CI: 0.90–1.62; HRQ3 = 1.48, 95 %CI: 1.10–1.99; HRQ4 = 1.58, 95 %CI: 1.13–2.23; p-trend = 3.1 × 10−3).The public transportation association was observed among those with higher NO2 (p-interaction = 0.02). Other commute categories were not associated with risk. ConclusionsCommuters residing in high-NO2 areas who often use public transportation could have elevated lung cancer risk compared to regular automobile users. These results warrant investigations into which component(s) of public transportation contribute to the observed association with increased lung cancer risk.

Mechanisms of the synergistic lung tumorigenic effect of arsenic and benzo(a)pyrene combined- exposure.

Humans are often exposed to mixtures of environmental pollutants especially environmental chemical carcinogens, representing a significant environmental health issue. However, our understanding on the carcinogenic effects and mechanisms of environmental carcinogen mixture exposures is limited and mostly relies on the findings from studying individual chemical carcinogens. Both arsenic and benzo(a)pyrene (BaP) are among the most common environmental carcinogens causing lung cancer and other types of cancer in humans. Millions of people are exposed to arsenic via consuming arsenic-contaminated drinking water and even more people are exposed to BaP via cigarette smoking and consuming BaP-contaminated food. Thus arsenic and BaP combined-exposure in humans is common. Previous epidemiology studies indicated that arsenic-exposed people who were cigarette smokers had significantly higher lung cancer risk than those who were non-smokers. Since BaP is one of the major carcinogens in cigarette smoke, it has been speculated that arsenic and BaP combined-exposure may play important roles in the increased lung cancer risk observed in arsenic-exposed cigarette smokers. In this review, we summarize important findings and inconsistencies about the co-carcinogenic effects and underlying mechanisms of arsenic and BaP combined-exposure and propose new areas for future studies. A clear understanding on the mechanism of co-carcinogenic effects of arsenic and BaP combined exposure may identify novel targets to more efficiently treat and prevent lung cancer resulting from arsenic and BaP combined-exposure.

Functional analysis of an enhancer flanked by four tobacco smoke‐responsive DNA methylation sites in the aryl hydrocarbon receptor repressor gene Samuel Jump 1,2 , Chunli Yan 1,2 , Ite Offringa 123 * 1 USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA, 2 Department of Surgery, 3 Department of Biochemistry and Molecular

Lung cancer is the leading cause for cancer-related deaths worldwide. Research suggests that lung cancers arising in smokers show many different molecular alterations compared to those in non-smokers. While mutations contribute to lung cancer development, environmental exposures also lead to epigenetic changes –changes in the decorations and protein occupancy of the DNA—which have been shown to increase lung cancer risk. We are thus focused on studying how epigenetic changes caused by tobacco smoke exposure affect the development of lung adenocarcinoma. Specifically, the objective is to better understand the significance of tobacco smoke-induced DNA hypomethylation near regulatory elements of the aryl hydrocarbon receptor repressor (AHRR) genein increasing lung cancer risk. Differential DNA methylation can be an epigenetic marker of regulatory elements and is usually inversely associated with activity of these elements. It can be associated with changes in expression levels of their respective tobacco smoke responsive genes like AHRR. Previous epigenome-wide association studies have identified hypomethylation of cg05575921 upon exposure to cigarette smoke (a CpG which flanks an enhancer located in the third intron of AHRR) as predictive of lung cancer risk (1,2). Due to the importance of detoxification, it is expected that multiple enhancers may drive AHRR leading to identification of other tobacco smoke-induced hypomethylated CpGs in AHRR. From the literature I identified four smoking-induced hypomethylated CpGs on the flanks of another enhancer (as marked by histone enhancer marks H3K4me1 and H3K27ac) potentially establishing a link between cigarette smoke, this enhancer, hypomethylation, and altered levels of AHRR expression (3,4,5,6). By using a modified version of the CRISPR/Cas9 system, we are deleting this enhancer from A549 lung cancer cells to test the connection between differential DNA methylation flanking this enhancer and changes in the activity AHRR or other genes within 1 megabase. Our analyses promise to shed light on the mechanism underlying the link between hypomethylation in AHRR and lung cancer risk.

Functional Analysis of the Enhancer at cg05575921, a DNA Methylation Site that is Tobacco Smoke‐Responsive and Highly Associated with Lung Cancer Risk

This project aims to investigate the molecular role of epigenetic changes from tobacco smoke exposure in the development of lung cancer, the largest cause of cancer-related deaths. The epigenome consists of the heritable chemical groups on the genome that regulate gene expression. One well-studied epigenetic mark is DNA methylation, which occurs at CpG dinucleotides and is usually associated with gene silencing. Environmental and lifestyle factors such as smoking can induce heritable alterations to the epigenome and can thereby influence disease risk. However, the mechanisms by which tobacco smoke exposure leads to increased lung cancer risk are not fully understood. Past studies have linked hypomethylation of cg05575921, a CpG in the aryl hydrocarbon receptor repressor (AHRR) gene, a regulator of the xenobiotic response pathway, as a strong indicator of lung cancer risk. Tobacco smoke exposure results in hypomethylation of cg05575921 in blood and lung tissue. Our previous research showed that cg05575921 flanks a tobacco smoke-inducible enhancer linked to the induction of AHRR expression. Our guiding hypothesis is that hypomethylation of cg05575921 is a byproduct of enhancer activation by tobacco smoke, and that it is the enhancer activity that has functional consequences, not the loss of methylation at cg05575921. To evaluate the functional role of this enhancer, we used CRISPR/Cas9 gene editing technology to generate monoclonal A549 cell lines with targeted DNA deletions of either the enhancer region, the CpG site adjacent to it, or a negative control region lacking regulatory marks. Resulting clones will be treated with cigarette smoke condensate (CSC) and analyzed for AHRR expression through whole-transcriptome mRNA sequencing (RNA-seq). Initial findings show a high rate of successful deletions in transfected cells, bolstering the technique's potential for studying enhancers’ roles in cancerous transformation. Thus far, clones in the enhancer deletion group have been screened via PCR for the desired deletion, further characterized via Sanger sequencing across deletion sites and heterozygous SNPs, exposed to CSC for 48 hours, and RNA has been subjected to RNA-seq. Analysis of RNA-seq data is ongoing. CpG deletion clones have been screened and sequenced and are ready to undergo CSC exposure. Negative control deletion clones have been generated and are growing in preparation for screening. Our analyses promise to shed light on the mechanism underlying the link between cg05575921 hypomethylation and lung cancer risk.