Variation In Lung Cancer Risk Research Articles

ES12.02 Defining High Risk

ES12.02 Defining High Risk

Metabolomics Profiles of Smokers from Two Ethnic Groups with Differing Lung Cancer Risk.

African American (AA) smokers are at a higher risk of developing lung cancer compared to whites. The variations in the metabolism of nicotine and tobacco-derived carcinogens in these groups were reported previously with the levels of nicotine metabolites and carcinogen-derived metabolites measured using targeted approaches. While useful, these targeted strategies are not able to detect global metabolic changes for use in predicting the detrimental effects of tobacco use and ultimately lung cancer susceptibility among smokers. To address this limitation, we have performed global untargeted metabolomics profiling in urine of AA and white smokers to characterize the pattern of metabolites, identify differentially regulated pathways, and correlate these profiles with the observed variations in lung cancer risk between these two populations. Urine samples from AA (n = 30) and white (n = 30) smokers were used for metabolomics analysis acquired in both positive and negative electrospray ionization modes. LC-MS data were uploaded onto the cloud-based XCMS online (http://xcmsonline.scripps.edu) platform for retention time correction, alignment, feature detection, annotation, statistical analysis, data visualization, and automated systems biology pathway analysis. The latter identified global differences in the metabolic pathways in the two groups including the metabolism of carbohydrates, amino acids, nucleotides, fatty acids, and nicotine. Significant differences in the nicotine degradation pathway (cotinine glucuronidation) in the two groups were observed and confirmed using a targeted LC-MS/MS approach. These results are consistent with previous studies demonstrating AA smokers with lower glucuronidation capacity compared to whites. Furthermore, the d-glucuronate degradation pathway was found to be significantly different between the two populations, with lower amounts of the putative metabolites detected in AA compared to whites. We hypothesize that the differential regulation of the d-glucuronate degradation pathway is a consequence of the variations in the glucuronidation capacity observed in the two groups. Other pathways including the metabolism of amino acids, nucleic acids, and fatty acids were also identified, however, the biological relevance and implications of these differences across ethnic groups need further investigation. Overall, the applied metabolomics approach revealed global differences in the metabolic networks and endogenous metabolites in AA and whites, which could be used and validated as a new potential panel of biomarkers that could be used to predict lung cancer susceptibility among smokers in population-based studies.

Geographical variation in lung cancer risk associated with road traffics in Jiading District, Shanghai

Few studies have investigated the spatial variation in road traffic indicators associated with lung cancer risk. The purpose of this study was to explore the relationship between road traffic-related indicators and lung cancer risk and to estimate its spatial variability. The population-based case control study was conducted, including all the newly diagnosed lung cancer patients (cases) and colorectal cancer patients (controls) in Jiading District, Shanghai from 2014 to 2016. Traffic intensity variable (traffic intensity in a 500 m buffer), residential distance to major road or highway, and greenness exposure at the residence were estimated for each individual. We conducted unconditional logistic regression with adjustment for age, sex, smoking status and NDVI values and geographically weighted logistic regression (GWLR). The clustering of lung cancer risk was analyzed by Bernoulli model of the SaTScan software. This study included 1461 lung cancer patients and 954 colorectal cancer patients. In multivariate logistic regression, smoking [OR 1.25 95% CI (1.15–1.35)], living <50 m from the major road [OR 1.43 95% CI (1.02–2.03)] were significantly associated with lung cancer risk. Residential Proximity to highway, residential greenness, and traffic intensity were not significantly associated with lung cancer risk. The GWLR model showed that the degree of correlation between residential proximity to major road and lung cancer risk varied geographically. The SaTScan results showed a lung cancer cluster in the southwest of Jiading District, Shanghai. Our study suggested that the distance from residence to the main road was significantly associated with lung cancer risk, which varied geographically. It is helpful to further study the traffic factors' spatial variation related to lung cancer risk and carry out reasonable regional planning.

Association of CYP2A6 activity with lung cancer incidence in smokers: The multiethnic cohort study.

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.

The role of NOD1/CARD4 and NOD2/CARD15 genetic variations in lung cancer risk.

NOD1/CARD4 and NOD2/CARD15 are members of the Nod-like receptor (NLR) family, and they contain a caspase recruitment domain (CARD). NLRs are located in the cytosol where they bind bacterial and viral ligands and play a key role in the innate and adaptive immune response, apoptosis, autophagy, and reactive oxygen species generation. NLR gene polymorphisms may shift the balance between pro- and anti-inflammatory cytokines and modulate the risk of infection, chronic inflammation, and cancer. NOD1/CARD4 and NOD2/CARD15 gene polymorphisms may also be associated with altered risks for many cancer types. The aim of our study was to evaluate the potential associations between lung cancer and NOD1/CARD4 and NOD2/CARD15 polymorphisms. The NOD1/CARD4 (rs5743336) and NOD2/CARD15 (rs2066847) SNPs were analyzed by PCR restriction fragment-length polymorphism analysis (PCR-RFLP) in 260 subjects (lung cancer patients: n = 160; healthy controls: n = 100) of Turkish origin. PCR products were digested with AvaI for rs5743336 and ApaI for rs2066847 and then visualized. Comparisons of the genotypes between control and lung cancer patients were performed by Chi-square tests. We found a significant difference in the genotypic distribution of the rs5743336 variant of NOD1/CARD4 between lung cancer patients and controls (p = 0.010, χ (2) = 9.220). However, we did not identify any statistically significant difference for the p.Leu1007fsX1008 (rs2066847) genotype of NOD2/CARD15 between groups (p > 0.05). According to our data, the rs5743336 variant of the NOD1/CARD4 gene may influence the diagnosis and treatment of lung cancer, whereas the rs2066847 variant of the NOD2/CARD15 gene is not associated with lung cancer risk in the Turkish population.

CEBPG Exhibits Allele-Specific Expression in Human Bronchial Epithelial Cells

Inter-individual variation in CCAAT/enhancer binding protein gamma (CEBPG) transcript expression in normal human bronchial epithelial cells (NBEC) is associated with predisposition to lung cancer. We hypothesize that this inter-individual variation is in part explained by cis-acting genetic variation in CEBPG. To test this hypothesis we measured transcript expression derived from each parental copy of CEBPG (ie, allele-specific expression; ASE). There was a significant 2.9-fold higher cell cycle-specific variation in ASE of CEBPG rs2772 A compared to C allele (P < 0.001). In 20% of NBEC samples, CEBPG rs2772 A allele was expressed on average 2.10 fold greater than rs2772 C allele. These data support the hypothesis that genetic variation in linkage disequilibrium with rs2772 influences regulation of CEBPG transcript expression through a trans-effect downstream of RNA polymerase II transcription and confirm that cis-acting genetic variation contributes to inter-individual variation in CEBPG transcript expression in NBEC, which is associated with variation in lung cancer risk.

Meta-analysis of the relationship between p21 Ser31Arg polymorphism and lung cancer susceptibility

The cyclin-dependent kinase inhibitor 1A (also known as p21) is thought to be involved in tumor development by mediating cell cycle arrest through the inhibition of cyclin/CDK activity. To explore the relationship of Ser31Arg polymorphism in the p21 gene with the risk of developing lung cancer, we performed an overall and stratified meta-analysis based on ethnicity, lung cancer subtypes and source of controls, with six eligible studies (2366 cases and 3320 controls). No significant variation in lung cancer risk was detected in any of the genetic models in the overall, and the ethnicity-based and cancer subtype-based subgroup analyses. However, in the subgroup analysis based on source of controls, significant opposite associations were observed; a significantly increased lung cancer risk was observed in the hospital-based control subgroup, while a significantly decreased lung cancer risk was detected in the mixed-source control and unknown-source control subgroups. In summary, based on our meta-analysis, p21 Ser31Arg polymorphism does not appear to act as an independent lung cancer risk factor and is more likely to act together with other genetic and non-genetic factors in the development of lung cancer; this needs further investigation.

Variation in lung cancer risk by smoky coal subtype in Xuanwei, China

Lung cancer rates in Xuanwei County have been among the highest in China for both males and females and have been causally associated with exposure to indoor smoky (bituminous) coal emissions that contain very high levels of polycyclic aromatic hydrocarbons. There are numerous coal mines across the County. Although lung cancer risk is strongly associated with the use of smoky coal as a whole, variation in risk by smoky coal subtype has not been characterized as yet. We conducted a population-based case-control study of 498 lung cancer cases and 498 controls, individually matched to case subjects on age (+/-2 years) and sex to examine risk by coal subtype. Odds ratios (ORs) and 95% confidence intervals (CIs) for coal subtype were calculated by conditional logistic regression, adjusting for potential confounders. Overall, smoky coal use was positively and statistically significantly associated with lung cancer risk, when compared with the use of smokeless coal or wood (OR = 7.7, 95% CI = 4.5-13.3). Furthermore, there was a marked heterogeneity in risk estimates for specific subtypes of smoky coal (test for heterogeneity: p = 5.17 x 10(-10)). Estimates were highest for coal of the Laibin (OR = 24.8, 95% CI = 12.4-49.6) and Longtan (OR = 11.6, 95% CI = 5.0-27.2) coal types and lower for coal from other subtypes. These findings strongly suggest that in Xuanwei and elsewhere, the carcinogenic potential of coal combustion products can exhibit substantial local variation by specific coal source.

CEBPG regulates ERCC5/XPG expression in human bronchial epithelial cells and this regulation is modified by E2F1/YY1 interactions

Marked inter-individual variation in lung cancer risk cannot be accounted for solely by cigarette smoke and other environmental exposures. Evidence suggests that variation in bronchial epithelial cell expression of key DNA repair genes plays a role. Variation in these genes correlates with variation in expression of CEBPG and E2F1 transcription factors. Here, we investigated the mechanistic basis for correlation of the DNA repair gene ERCC5 (previously known as XPG) with CEBPG and E2F1. CEBPG expression vector transfected into H23 or H460 cell lines up-regulated endogenous ERCC5 and also luciferase from a reporter construct containing 589 bp of ERCC5 5' regulatory region. A recognition site for CEBPG and a region containing sites for YY1 on the sense strand and E2F1 on the anti-sense strand participated in CEBPG up-regulation of ERCC5. CEBPG, E2F1 and YY1 binding to their respective sites were confirmed by electrophoretic mobility shift assay. Thus, we conclude that CEBPG regulates ERCC5 expression and this regulation is modified by E2F1/YY1 interactions. Several polymorphisms have been identified in these regions and, based on the data presented here, it is reasonable to hypothesize that they may contribute to risk for bronchogenic carcinoma.

Risk of second cancer after chronic lymphocytic leukemia

Smoking is not considered a risk factor for chronic lymphocytic leukemia (CLL) yet increased lung cancer risk has been reported for these patients. Little data exist on the temporal variation in lung cancer risk after CLL, or its histological composition. We investigated the occurrence of second cancers in a large cohort of CLL patients with particular emphasis on lung cancer and its major subtypes. We followed all patients diagnosed with CLL in Denmark in the period 1943-2003 (n = 12,373) for the occurrence of second cancers. The relative risk was expressed as the standardized incidence ratio (SIR), i.e. the ratio of observed to expected number of cancers, based on incidence rates for the Danish population. During follow-up 1,105 cancers occurred among the CLL patients (SIR = 1.59 (95% CI 1.50-1.69)). SIR for all cancers combined remained elevated more than 10 years after CLL (SIR = 1.80 (1.56-2.08)). Lung cancer occurred in 141 patients (SIR = 1.61 (1.37-1.90)). The relative risk of lung cancer did not vary by gender, or time of follow-up, but was higher in younger (SIR(<60 years) = 2.22 (1.62-3.06)) than in older (SIR(70-79 years) = 1.21 (0.88-1.68)) age-groups. Elevated risks were observed for adenocarcinoma (SIR = 2.20 (1.57-3.08)) and squamous cell carcinoma (SIR = 1.52 (1.06-2.17)) of the lung. We speculate that shared genetic risk factors may explain the accumulation of lung and other cancers in CLL patients.

Variations in lung cancer risk among smokers.

Although there is no proven benefit associated with screening for lung cancer, screening programs are attracting many individuals who perceive themselves to be at high risk due to smoking. We sought to determine whether the risk of lung cancer varies predictably among smokers. We used data on 18 172 subjects enrolled in the Carotene and Retinol Efficacy Trial (CARET)-a large, randomized trial of lung cancer prevention-to derive a lung cancer risk prediction model. Model inputs included the subject's age, sex, asbestos exposure history, and smoking history. We assessed the model's calibration by comparing predicted and observed rates of lung cancer across risk deciles and validated it by assessing the extent to which a model estimated on data from five CARET study sites could predict events in the sixth study site. We then applied the model to evaluate the risk of lung cancer among smokers enrolled in a study of lung cancer screening with computed tomography (CT). The model was internally valid and well calibrated. Ten-year lung cancer risk varied greatly among participants in the CT study, from 15% for a 68-year-old man who has smoked two packs per day for 50 years and continues to smoke, to 0.8% for a 51-year-old woman who smoked one pack per day for 28 years before quitting 9 years earlier. Even among the subset of CT study participants who would be eligible for a clinical trial of cancer prevention, risk varied greatly. The risk of lung cancer varies widely among smokers. Accurate risk prediction may help individuals who are contemplating voluntary screening to balance the potential benefits and risks. Risk prediction may also be useful for researchers designing clinical trials of lung cancer prevention.