The cause of lung cancer is generally attributed to tobacco smoking. However lung cancer in never smokers accounts for 10 to 25% of all lung cancer cases. Arsenic, asbestos and radon are three prominent non-tobacco carcinogens strongly associated with lung cancer. Exposure to these agents can lead to genetic and epigenetic alterations in tumor genomes, impacting genes and pathways involved in lung cancer development. Moreover, these agents not only exhibit unique mechanisms in causing genomic alterations, but also exert deleterious effects through common mechanisms, such as oxidative stress, commonly associated with carcinogenesis. This article provides a comprehensive review of arsenic, asbestos, and radon induced molecular mechanisms responsible for the generation of genetic and epigenetic alterations in lung cancer. A better understanding of the mode of action of these carcinogens will facilitate the prevention and management of lung cancer related to such environmental hazards.
In this chapter we review the epidemiology of lung cancer incidence and mortality among never smokers/ nonsmokers and describe the never smoker lung cancer risk models used by CISNET modelers. Our review focuses on those influences likely to have measurable population impact on never smoker risk, such as secondhand smoke, even though the individual-level impact may be small. Occupational exposures may also contribute importantly to the population attributable risk of lung cancer. We examine the following risk factors in this chapter: age, environmental tobacco smoke, cooking fumes, ionizing radiation including radon gas, inherited genetic susceptibility, selected occupational exposures, preexisting lung disease, and oncogenic viruses. We also compare the prevalence of never smokers between the three CISNET smoking scenarios and present the corresponding lung cancer mortality estimates among never smokers as predicted by a typical CISNET model.
Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers’ lung carcinomas remain to a large extent unclear.
Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets.
Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking.
Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history.
Lung cancer; Smoking; Gene expression analysis; Adenocarcinoma; EGFR; Never-smokers; Immune response
Lung cancer is the leading cause of cancer-related deaths in the Western world. Lungs can be affected by a number of histologically diverse malignancies. Nonetheless, the vast majority of lung cancers are classified as non-small cell lung cancer (NSCLC). Despite extensive research on different therapeutic regimens, the overall 5-year survival of patients diagnosed with NSCLC (all stages) is a dismal 15%. Although strongly correlated with tobacco smoke, there is an increasing NSCLC morbidity in individuals who have never smoked. The pattern of genetic lesions found in NSCLC derived from smokers and never-smokers appears to be different. This fact led to the hypothesis that different, still unidentified carcinogens are responsible for lung cancer onset in never-smokers. All the above considerations compel the scientific community to find novel therapeutic targets to fight such a deadly disease.
In recent years critical pathways governing embryonic development have been increasingly linked to cancer. Here we will focus on the role of Notch signaling in lung cancer. Notch receptors’ activity can be blocked following different strategies, thus representing a promising alternative/complement to the arsenal of therapeutic strategies currently used to treat lung cancer.
lung cancer; cancer progenitor cells; Notch signaling; hypoxia; cancer stem cells; Notch signaling inhibition
More than 161,000 lung cancer deaths are projected to occur in the U.S. in 2008. Of these, an estimated 10–15% will be caused by factors other than active smoking, corresponding to 16,000–24,000 deaths annually. Thus lung cancer in never smokers would rank among the most common causes of cancer mortality in the U.S. if considered to be a separate category. Slightly more than half of the lung cancers caused by factors other than active smoking occur in never smokers. As summarized in the accompanying article, lung cancers that occur in never smokers differ from those that occur in smokers in their molecular profile and response to targeted therapy. These recent laboratory and clinical observations highlight the importance of defining the genetic and environmental factors responsible for the development of lung cancer in never-smokers. This article summarizes available data on the clinical epidemiology of lung cancer in never smokers, and the several environmental risk factors that population-based research has implicated in the etiology of these cancers. Primary factors closely tied to lung cancer in never smokers include exposure to known and suspected carcinogens including radon, second-hand tobacco smoke, and other indoor air pollutants. Several other exposures have been implicated. However, a large fraction of lung cancers occurring in never-smokers cannot be definitively associated with established environmental risk factors, highlighting the need for additional epidemiologic research in this area.
Cigarette smoking by children and adolescents continues to be prevalent, and this fact represents a major public health problem and challenge. Epidemiologic work has previously suggested that exposure of the lung to tobacco carcinogens at an early age may be an independent risk factor for lung cancer. Recent studies at the molecular and cellular levels are consistent with this, now suggesting that early exposure enhances DNA damage and is associated with the induction of DNA alterations in specific chromosomal regions. In this paper we hypothesize that adolescence, which is known to be the period of greatest development for the lung, may constitute a "critical period" in which tobacco carcinogens can induce fields of genetic alterations that make the early smoker more susceptible to the damaging effects of continued smoking. The fact that lung development differs by sex might also contribute to apparent gender differences in lung cancer susceptibility. Because this hypothesis has important implications for health policy and tobacco control, additional resources need to be devoted to its further evaluation. Targeted intervention in adolescent smoking may yield even greater reductions in lung cancer occurrence than otherwise anticipated.
Tobacco smoke contains many mutagenic and carcinogenic chemicals. Both whole tobacco smoke and extracts induce tumors in experimental animals. Work with carcinogen-macromolecule adducts provided evidence for the action of specific chemicals. Molecular epidemiology studies suggested that point mutations in tumor-suppressor genes (e.g., p53) and oncogenes (e.g., ras) may be specific both for the type of tumor and for the critical environmental exposure. The consistency among investigations on oncogene/tumor-suppressor gene mutations in lung cancer (and other tobacco-related cancers) in smokers is highly suggestive, although we still lack information about the time sequence between exposure, gene mutation, and cancer onset. Current work that deserves emphasis includes investigations revealing that lungs of smokers contain benzo[a]pyrene diol-epoxide-guanine DNA adducts, which are in accordance with the type of mutations found in K-ras or p53 genes (G to T transversions). In addition, DNA in human exfoliated bladder cells showed a derivative of 4-aminobiphenyl as a main adduct; there was also an association between smoking habits (amount and type of tobacco) and the levels of both DNA adducts and hemoglobin adducts formed by aromatic amines. Increasing evidence indicates that genetically based metabolic polymorphisms exert a role in modulating individual susceptibility to the action of tobacco carcinogens. Overall, the weight of evidence strongly supports the causal nature of the association between smoking and cancer and falsifies Fisher's hypothesis that the association was due to confounding by genetic predisposition.
The objective of the current study was to estimate the risk of lung cancer attributable to occupational factors and not due to tobacco. At 24 hospitals in nine metropolitan areas in the United States, 1793 male lung cancer cases were matched for race, age, hospital, year of interview, and cigarette smoking (never smoker, ex-smoker, smoker (1-19 and > or = 20 cigarettes per day)) to two types of controls (cancer and non-cancer hospital patients). Information on usual occupation, exposure to specific potential carcinogens, and cigarette smoking was obtained by interview. Risk of lung cancer was increased significantly for electricians; sheetmetal workers and tinsmiths; bookbinders and related printing trade workers; cranemen, derrickmen, and hoistmen; moulders, heat treaters, annealers and other heated metal workers; and construction labourers. All of these occupations are potentially exposed to known carcinogens. Odds ratios (ORs) were increased for exposure to coal dust (adjusted OR = 1.5; 95% confidence interval (95% CI) 1.1-2.1). After stratification, this association was statistically significant only after 10 or more years of exposure. Lung cancer was also related to exposure to asbestos (adjusted OR = 1.8; 95% CI 1.5-2.2). The ORs increased with increasing duration of exposure to asbestos for all smoking categories except for current smokers of 1-19 cigarettes per day. The statistical power to detect ORs among occupations that were previously reported to be at increased risk of lung cancer but that failed to show an OR of at least 1.5 in the current study was small. The cumulative population attributable risk (PAR) of lung cancer due to occupation was 9.2%. It is concluded that occupational factors play an important part in the development of lung cancer independently of cigarette smoking. Because occupations at high risk of lung cancer were under-represented, the cumulative PAR of the present study is likely to be an underestimate of the true contribution of occupation to risk of lung cancer.
Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n = 20), smokers without lung cancer (SNC, n = 24), and never smokers (NS, n = 8). Functional enrichment analysis showed that the NRF2-mediated, antioxidant response element (ARE)-regulated genes, were significantly lower in SC, when compared with expression levels in SNC. Importantly, we found that the expression of MAFG (a binding partner of NRF2) was correlated with the expression of ARE genes, suggesting MAFG levels may limit target gene induction. Bioinformatically we identified single nucleotide polymorphisms (SNPs) in putative ARE genes and to test the impact of genetic variation, we genotyped these putative regulatory SNPs and other tag SNPs in selected NRF2 pathway genes. Sequencing MAFG locus, we identified 30 novel SNPs and two were associated with either gene expression or lung cancer status among smokers. This work demonstrates an analysis approach that integrates bioinformatics pathway and transcription factor binding site analysis with genotype, gene expression and disease status to identify SNPs that may be associated with individual differences in gene expression and/or cancer status in smokers. These polymorphisms might ultimately contribute to lung cancer risk via their effect on the airway gene expression response to tobacco-smoke exposure.
Several countries are discussing new legislation on the ban of smoking in public places, and on the acceptable levels of traffic-related air pollutants. It is therefore useful to estimate the burden of disease associated with indoor and outdoor air pollution.
We have estimated exposure to Environmental Tobacco Smoke (ETS) and to air pollution in never smokers and ex-smokers in a large prospective study in 10 European countries (European Prospective Investigation into Cancer and Nutrition)(N = 520,000). We report estimates of the proportion of lung cancers attributable to ETS and air pollution in this population.
The proportion of lung cancers in never- and ex-smokers attributable to ETS was estimated as between 16 and 24%, mainly due to the contribution of work-related exposure. We have also estimated that 5–7% of lung cancers in European never smokers and ex-smokers are attributable to high levels of air pollution, as expressed by NO2 or proximity to heavy traffic roads. NO2 is the expression of a mixture of combustion (traffic-related) particles and gases, and is also related to power plants and waste incinerator emissions.
We have estimated risks of lung cancer attributable to ETS and traffic-related air pollution in a large prospective study in Europe. Information bias can be ruled out due to the prospective design, and we have thoroughly controlled for potential confounders, including restriction to never smokers and long-term ex-smokers. Concerning traffic-related air pollution, the thresholds for indicators of exposure we have used are rather strict, i.e. they correspond to the high levels of exposure that characterize mainly Southern European countries (levels of NO2 in Denmark and Sweden are closer to 10–20 ug/m3, whereas levels in Italy are around 30 or 40, or higher).
Therefore, further reduction in exposure levels below 30 ug/m3 would correspond to additional lung cancer cases prevented, and our estimate of 5–7% is likely to be an underestimate. Overall, our prospective study draws attention to the need for strict legislation concerning the quality of air in Europe.
Lung cancer is the most common cause of cancer-related deaths. Tobacco smoke exposure is the strongest aetiological factor associated with lung cancer. In this study, using serial analysis of gene expression (SAGE), we comprehensively examined the effect of active smoking by comparing the transcriptomes of clinical specimens obtained from current, former and never smokers, and identified genes showing both reversible and irreversible expression changes upon smoking cessation.
Twenty-four SAGE profiles of the bronchial epithelium of eight current, twelve former and four never smokers were generated and analyzed. In total, 3,111,471 SAGE tags representing over 110 thousand potentially unique transcripts were generated, comprising the largest human SAGE study to date. We identified 1,733 constitutively expressed genes in current, former and never smoker transcriptomes. We have also identified both reversible and irreversible gene expression changes upon cessation of smoking; reversible changes were frequently associated with either xenobiotic metabolism, nucleotide metabolism or mucus secretion. Increased expression of TFF3, CABYR, and ENTPD8 were found to be reversible upon smoking cessation. Expression of GSK3B, which regulates COX2 expression, was irreversibly decreased. MUC5AC expression was only partially reversed. Validation of select genes was performed using quantitative RT-PCR on a secondary cohort of nine current smokers, seven former smokers and six never smokers.
Expression levels of some of the genes related to tobacco smoking return to levels similar to never smokers upon cessation of smoking, while expression of others appears to be permanently altered despite prolonged smoking cessation. These irreversible changes may account for the persistent lung cancer risk despite smoking cessation.
It is now recognized that exposure to environmental tobacco smoke (ETS) in the workplace and other settings outside the home may be equally as important as residential ETS exposure. This review examines the sources of misclassification in the assessment of workplace ETS exposure in questionnaire-based epidemiologic studies. Cogent to this discussion is the role of misclassification of ever smokers as never smokers, which is important in studies of both workplace and residential ETS exposure and lung cancer and is discussed first. The collective evidence from studies that have used direct or indirect approaches to estimate smoker misclassification shows that although some misclassification of ever smokers as never smokers exists in studies of ETS and lung cancer, the potential bias from the misclassification of smokers is unlikely to explain the observed increased risk of lung cancer associated with ETS exposure.
Lung cancer is the leading cause of cancer death in men and women worldwide, with over a million deaths annually. Tobacco smoke is the major etiologic risk factor for lung cancer in current or previous smokers and has been strongly related to certain types of lung cancer, such as small cell lung carcinoma and squamous cell lung carcinoma. In recent years, there has been an increased incidence of lung adenocarcinoma. This change is strongly associated with changes in smoking behavior and cigarette design. Carcinogens present in tobacco products and their intermediate metabolites can activate multiple signaling pathways that contribute to lung cancer Carcinogenesis. In this review, we summarize the smoking-activated signaling pathways involved in lung cancer.
Lung cancer; signaling pathways; Carcinogenesis; cigarette smoking
Recently published evidence indicates that involuntary smoking causes an increased risk of lung cancer among nonsmokers. Information was compiled on the proportion of people who had never smoked among victims of lung cancer, the risk of lung cancer for nonsmokers married to smokers and the prevalence of such exposure. On the basis of these data we estimate that 50 to 60 of the deaths from lung cancer in Canada in 1985 among people who had never smoked were caused by spousal smoking; about 90% occurred in women. The total number of deaths from lung cancer attributable to exposure to tobacco smoke from spouses and other sources (mainly the workplace) was derived by applying estimated age- and sex-specific rates of death from lung cancer attributable to such exposure to the population of Canadians who have never smoked; about 330 deaths from lung cancer annually are attributable to such exposure.
Cigarette smoking is the major cause for lung cancer but genetic factors also affect susceptibility. We studied families that included multiple relatives affected by lung cancer. Results from linkage analysis showed strong evidence that a region of chromosome 6q affects lung cancer risk. To characterize the effects that this region of chromosome 6q region has on lung cancer risk we identified a haplotype that segregated with lung cancer. We then performed Cox regression analysis to estimate the differential effects that smoking behaviors have upon lung cancer risk according to whether each individual carried a risk-associated haplotype or could not be classified and was assigned unknown haplotypic status. We divided smoking exposures into never smokers, light smokers (<20 pack years), moderate smokers (20-<40 pack years) and heavy smokers (40 or more pack years). Comparing results according to smoking behavior stratified by carrier status, compared to never smokers, there was weakly increasing risk for increasing smoking behaviors, with the hazards ratios being 3.44, 4.91, and 5.18 respectively for light, moderate or heavy smokers, while among the individuals from families without the risk haplotype, the risks associated with smoking increased strongly with exposure, the hazards ratios being respectively 4.25, 9.17 and 11.89 for light, moderate and heavy smokers. The never smoking carriers had a 4.71 fold higher risk than the never smoking individuals without known risk haplotypes. These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers.
Cigarette smoke produces a molecular “field of injury” in epithelial cells lining the respiratory tract. However, the specific signaling pathways that are altered in the airway of smokers and the signaling processes responsible for the transition from smoking-induced airway damage to lung cancer remain unknown. In this study, we use a genomic approach to study the signaling processes associated with tobacco smoke exposure and lung cancer. First, we developed and validated pathway-specific gene expression signatures in bronchial airway epithelium that reflect activation of signaling pathways relevant to tobacco-exposure including ATM, BCL2, GPX1, NOS2, IKBKB, and SIRT1. Using these profiles and four independent gene expression datasets, we found that SIRT1 activity is significantly up-regulated in cytologically normal bronchial airway epithelial cells from active smokers compared to non-smokers. In contrast, this activity is strikingly down-regulated in non-small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and down-regulation of SIRT1 activity is confined to tumors from smokers. Decreased activity of SIRT1 was validated using genomic analyses of mouse models of lung cancer and biochemical testing of SIRT1 activity in patient lung tumors. Together, our findings indicate a role of SIRT1 in response to smoke and a potential role in repressing lung cancer. Further, our findings suggest that the airway gene-expression signatures derived in this study can provide novel insights into signaling pathways altered in the “field of inury” induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer.
Aside from tobacco carcinogen metabolism, isothiocyanates (ITC) from cruciferous vegetables may induce apoptosis or steroid metabolism to reduce lung cancer risk. To separate the effect of these divergent mechanisms of action, we investigated the association between urinary ITC levels and lung cancer risk among non-smoking women.
We conducted a nested case-control within the Shanghai Women’s Health Study. Subjects included 209 incident lung cancer cases who never used tobacco, and 787 individually matched non-smoking controls. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) summarizing the association between urinary ITC levels and lung cancer. Secondary analyses stratified the ITC-lung cancer analyses by menopausal status, exposure to environmental tobacco smoke, and GSTM1 and GSTT1 genotypes.
Urinary ITC levels were not significantly associated with lower lung cancer risk among non-smoking women, regardless of exposure to environmental tobacco smoke or menopausal status. Furthermore, this association was not modified by GSTT1 genotype. However, an inverse association was suggested among women with a GSTM1-positive genotype (Q1: OR=1.0 (reference); Q2: OR=0.35 (0.14, 0.89); Q3: OR=0.47 (0.20, 1.10); Q4: OR=0.63 (0.35, 1.54), p-trend = 0.38)). In contrast, lung cancer risk was positively associated with urinary ITC levels among women with the GSTM1-null genotype (Q1: OR=1.0 (reference); Q2: OR=1.67 (0.80, 3.50); Q3: OR=1.54 (0.71, 3.33); Q4: OR=2.22 (1.05, 4.67), p-trend = 0.06)).
Urinary ITC levels were not associated overall with lower lung cancer risk among non-smoking women, but secondary analyses suggested an interaction between urinary ITC levels, GSTM1 genotype, and lung cancer risk.
isothiocyanate; lung neoplasm; diet; genetic susceptibility; women
Cigarette smoke creates a molecular field of injury in epithelial cells that line the respiratory tract. We hypothesized that transcriptome sequencing (RNA-Seq) will enhance our understanding of the field of molecular injury in response to tobacco smoke exposure and lung cancer pathogenesis by identifying gene expression differences not interrogated or accurately measured by microarrays. We sequenced the high-molecular-weight fraction of total RNA (>200 nt) from pooled bronchial airway epithelial cell brushings (n = 3 patients per pool) obtained during bronchoscopy from healthy never smoker (NS) and current smoker (S) volunteers and smokers with (C) and without (NC) lung cancer undergoing lung nodule resection surgery. RNA-Seq libraries were prepared using 2 distinct approaches, one capable of capturing non-polyadenylated RNA (the prototype NuGEN Ovation RNA-Seq protocol) and the other designed to measure only polyadenylated RNA (the standard Illumina mRNA-Seq protocol) followed by sequencing generating approximately 29 million 36 nt reads per pool and approximately 22 million 75 nt paired-end reads per pool, respectively. The NuGEN protocol captured additional transcripts not detected by the Illumina protocol at the expense of reduced coverage of polyadenylated transcripts, while longer read lengths and a paired-end sequencing strategy significantly improved the number of reads that could be aligned to the genome. The aligned reads derived from the two complementary protocols were used to define the compendium of genes expressed in the airway epithelium (n = 20,573 genes). Pathways related to the metabolism of xenobiotics by cytochrome P450, retinol metabolism, and oxidoreductase activity were enriched among genes differentially expressed in smokers, whereas chemokine signaling pathways, cytokine–cytokine receptor interactions, and cell adhesion molecules were enriched among genes differentially expressed in smokers with lung cancer. There was a significant correlation between the RNA-Seq gene expression data and Affymetrix microarray data generated from the same samples (P < 0.001); however, the RNA-Seq data detected additional smoking- and cancer-related transcripts whose expression was were either not interrogated by or was not found to be significantly altered when using microarrays, including smoking-related changes in the inflammatory genes S100A8 and S100A9 and cancer-related changes in MUC5AC and secretoglobin (SCGB3A1). Quantitative real-time PCR confirmed differential expression of select genes and non-coding RNAs within individual samples. These results demonstrate that transcriptome sequencing has the potential to provide new insights into the biology of the airway field of injury associated with smoking and lung cancer. The measurement of both coding and non-coding transcripts by RNA-Seq has the potential to help elucidate mechanisms of response to tobacco smoke and to identify additional biomarkers of lung cancer risk and novel targets for chemoprevention.
Though tobacco smoking is the primary risk factor for lung cancer, a significant fraction of lung cancer deaths occur in lifetime non-smokers. In this paper, we calculate the burden of lung cancer in never-smokers attributable to previously identified risk factors in North America, Europe, and China, using population-based estimates of exposure prevalence and estimates of relative risk derived from recently published meta-analyses. Population attributable fractions (PAFs) for individual risk factors ranged from 0.40% to 19.93%. Due to differences in the prevalence of exposures, the PAFs associated with several of the risk factors varied greatly by geographical region. Exposure to the selected risk factors appeared to explain a much larger proportion of lung cancer cases in never-smokers in China than in Europe and North America. Our results demonstrate the geographic variability of the epidemiology of lung cancer in never-smokers, and highlight the need for further research in this area, particularly in Europe and North America.
lung cancer; population attributable fraction; non-smokers
Lung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 SNPs in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke Another promising candidate was a SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-β superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment, (second hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.
lung cancer; never smokers; inflammation genes; sidestream exposure
Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung carcinogens. The classic mechanisms of carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This paper discusses certain features of this mechanism including the role of nicotine and its receptors; lung carcinogens, co-carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers’ lungs; and biomarkers of nicotine and carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year.
tobacco smoke; carcinogens; DNA adducts; nicotine
Tobacco smoking remains the most established cause of lung carcinogenesis and other disease processes. Over the last 50 years, tobacco refinement and the introduction of filters have brought a change in histology, and now adenocarcinoma has become the most prevalent subtype. Over the last decade, smoking also has emerged as a strong prognostic and predictive patient characteristic along with other variables. This article briefly reviews scientific facts about tobacco, and the process and molecular pathways involved in lung carcinogenesis in smokers and never-smokers. The evidence from randomised trials about tobacco smoking’s impact on lung cancer outcomes is also reviewed.
Tobacco Smoking; Lung Neoplasms; Nicotine; EML4 ALK fusion protein, human; K-Ras Gene; Receptor, Epidermal Growth Factor; Carcinogens
Tobacco smoking causes millions of cancer deaths annually. Tobacco smoke is a complex mixture of thousands of chemicals including many known animal carcinogens. Because many carcinogens from DNA adducts in target animal or human tissues, the detection of the formation of adducts using such methods as postlabeling, immunoassay, fluorescence spectroscopy, and mass spectrometry is a means of monitoring human exposure to tobacco carcinogens. Smokers are at increased risk of cancer in many organs, and studies have revealed either specific adducts related to smoking or increased levels of adducts in the lung, bronchus, larynx, bladder, cervix, and oral mucosa of smokers. In a limited number of studies, the adducts and the carcinogens responsible for them have been identified. Some studies have demonstrated higher levels of adducts in the white blood cells of smokers, while other studies indicate other sources of genotoxic agents, including diet, can contribute to the DNA damage observed in these cells.
Lung cancer patients with mutations in EGFR tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke.
This hypothesis was investigated by analyzing EGFR mutations in seventy lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive-smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic.
Overall, the frequency of EGFR mutation was 41% [95% Confidence Interval (CI): 32-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors.
The results suggest that EGFR mutations are common in female, never-smoking, lung cancer cases from the U.S, and EGFR mutations are unlikely due to exposure to radon or passive-smoking.
EGFR mutations; never-smokers; lung cancer; radon; passive-smoking; second hand smoke; tobacco smoke
Many case-control studies have been undertaken to assess whether and to what extent residential radon exposure is a risk factor for lung cancer. Nearly all these studies have been conducted in populations including smokers and nonsmokers. In this paper, we show that, depending on the nature of the joint effect of radon and tobacco on lung cancer risk, it may be very difficult to detect a main effect due to radon in mixed smoking and nonsmoking populations. If the joint effect is closer to additive than multiplicative, the most cost-effective way to achieve adequate statistical power may be to conduct a study among never-smokers. Because the underlying joint effect is unknown, and because many studies have been carried out among mixed smoker and nonsmoker populations, it would be desirable to conduct some studies with adequate power among never-smokers only.