Michael W. Marcus

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

Background Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01–1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15–2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79–1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84–0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25–2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

Unique volatolomic signatures of TP53 and KRAS in lung cells

Background:Volatile organic compounds (VOCs) are potential biomarkers for cancer detection in breath, but it is unclear if they reflect specific mutations. To test this, we have compared human bronchial epithelial cell (HBEC) cell lines carrying the KRASV12 mutation, knockdown of TP53 or both with parental HBEC cells.Methods:VOC from headspace above cultured cells were collected by passive sampling and analysed by thermal desorption gas chromatography mass spectrometry (TD-GC–MS) or sensor array with discriminant factor analysis (DFA).Results:In TD-GC–MS analysis, individual compounds had limited ability to discriminate between cell lines, but by applying DFA analysis combinations of 20 VOCs successfully discriminated between all cell types (accuracies 80–100%, with leave-one-out cross validation). Sensor array detection DFA demonstrated the ability to discriminate samples based on their cell type for all comparisons with accuracies varying between 77% and 93%.Conclusions:Our results demonstrate that minimal genetic changes in bronchial airway cells lead to detectable differences in levels of specific VOCs identified by TD-GC–MS or of patterns of VOCs identified by sensor array output. From the clinical aspect, these results suggest the possibility of breath analysis for detection of minimal genetic changes for earlier diagnosis or for genetic typing of lung cancers.

Welding and lung cancer in a pooled analysis of case-control studies.

Several epidemiologic studies have indicated an increased risk of lung cancer among welders. We used the SYNERGY project database to assess welding as a risk factor for developing lung cancer. The database includes data on 15,483 male lung cancer cases and 18,388 male controls from 16 studies in Europe, Canada, China, and New Zealand conducted between 1985 and 2010. Odds ratios and 95% confidence intervals between regular or occasional welding and lung cancer were estimated, with adjustment for smoking, age, study center, and employment in other occupations associated with lung cancer risk. Overall, 568 cases and 427 controls had ever worked as welders and had an odds ratio of developing lung cancer of 1.44 (95% confidence interval: 1.25, 1.67) with the odds ratio increasing for longer duration of welding. In never and light smokers, the odds ratio was 1.96 (95% confidence interval: 1.37, 2.79). The odds ratios were somewhat higher for squamous and small cell lung cancers than for adenocarcinoma. Another 1,994 cases and 1,930 controls had ever worked in occupations with occasional welding. Work in any of these occupations was associated with some elevation of risk, though not as much as observed in regular welders. Our findings lend further support to the hypothesis that welding is associated with an increased risk of lung cancer.

The contribution of risk prediction models to early detection of lung cancer.

Low‐dose computed tomography screening is a strategy for early diagnosis of lung cancer. The success of such screening will be dependent upon identifying populations at sufficient risk in order to maximise the benefit‐to‐harm ratio of the intervention. To facilitate this, the lung cancer risk prediction community has established several risk models with good predictive performance. This review focuses on current progress in risk modelling for lung cancer prediction, with some views on future development. J. Surg. Oncol. 2013 108:304–311.

Fine-mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci

Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000×) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73×10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64×10(-6)), rs112290073 (OR = 1.85, P = 1.27×10(-5)), rs138895564 (OR = 2.16, P = 2.06×10(-5); among young cases, OR = 3.77, P = 8.41×10(-4)). In addition, we found that rs139852726 (P = 1.44×10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84×10(-7)) and lung cancer (P = 2.37×10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.

LLPi: Liverpool Lung Project Risk Prediction Model for Lung Cancer Incidence.

Identification of high-risk individuals will facilitate early diagnosis, reduce overall costs, and also improve the current poor survival from lung cancer. The Liverpool Lung Project prospective cohort of 8,760 participants ages 45 to 79 years, recruited between 1998 and 2008, was followed annually through the hospital episode statistics until January 31, 2013. Cox proportional hazards models were used to identify risk predictors of lung cancer incidence. C-statistic was used to assess the discriminatory accuracy of the models. Models were internally validated using the bootstrap method. During mean follow-up of 8.7 years, 237 participants developed lung cancer. Age [hazard ratio (HR), 1.04; 95% confidence interval (CI), 1.02–1.06], male gender (HR, 1.48; 95% CI, 1.10–1.98), smoking duration (HR, 1.04; 95% CI, 1.03–1.05), chronic obstructive pulmonary disease (HR, 2.43; 95% CI, 1.79–3.30), prior diagnosis of malignant tumor (HR, 2.84; 95% CI, 2.08–3.89), and early onset of family history of lung cancer (HR, 1.68; 95% CI, 1.04–2.72) were associated with the incidence of lung cancer. The LLPi risk model had a good calibration (goodness-of-fit χ2 7.58, P = 0.371). The apparent C-statistic was 0.852 (95% CI, 0.831–0.873) and the optimism-corrected bootstrap resampling C-statistic was 0.849 (95% CI, 0.829–0.873). The LLPi risk model may assist in identifying individuals at high risk of developing lung cancer in population-based screening programs. Cancer Prev Res; 8(6); 570–5. ©2015 AACR.

The causal relevance of body mass index in different histological types of lung cancer: A Mendelian randomization study

Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m2) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 × 10−3) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma.

Trends and regional variation in the incidence of head and neck cancers in England: 2002 to 2011.

Recent studies show an increased incidence of head and neck cancers worldwide. The present study evaluated the trend in the incidence of head and neck cancers in England during 2002-2011. Data were extracted from the database of Office for National Statistics. The study population was categorised according to age, residential area, gender and cancer sub-types. Overall trend in incidence of head and neck cancer and some subtypes were examined using Poisson regression models. In total, 71,457 head and neck cancers were registered in England between 2002 and 2011 and 68% of patients were males. Statistically significant increases in incidence of 27.0 and 32.4% were documented in males and females, respectively (p<0.001) with the largest increase in the 60+ age category. Potentially HPV-associated cancers, oral cavity cancers and laryngeal cancers increased by 47.1, 24.1 and 1.7% in males and 37.5, 25.5 and 7.7% in females, respectively (p<0.001). Regional differences were also noted with the highest incidence (18.0 and 17.0 per 100,000, respectively) in the North East and North West of England. Our results for England showed an increase in the incidence of both oral cavity and oropharyngeal cancer in both genders, whilst laryngeal cancer incidence remained stable.

Electronic cigarette use and risk perception in a Stop Smoking Service in England

Abstract Introduction: Electronic cigarette (e-cigarette) use rose substantially within the UK in recent years but currently, Stop Smoking Services in England do not prescribe them due to a lack of regulation. Previous research has examined e-cigarette use and attitudes within English Stop Smoking Services using samples of practitioners and managers; the current study recruited a sample of service users. Methods: Participants (N = 319) aged 18–60 years old were recruited from Roy Castle FagEnds, Liverpool, England (Stop Smoking Service). A cross-sectional questionnaire was completed, which recorded demographic variables, e-cigarette use alongside risk perception, and lastly, smoking behaviour i.e. smoking duration, cigarettes per day, and nicotine dependence. Results: Most participants were female (57.1%), current smokers (53.0%), and current or former e-cigarette users (51.7%). Participants who perceived e-cigarettes as less harmful than smoked tobacco were more likely to have smoked fewer cigarettes per day (p = 0.008). Furthermore, those who felt uncertain whether e-cigarettes were safer than smoked tobacco, were less likely to have tried them (p < 0.001). Conclusion: This study suggests that e-cigarette use is becoming common among users of Stop Smoking Services (despite e-cigarettes being unavailable from such services) and that e-cigarette risk perception is related to e-cigarette status. The results highlight the importance of providing smokers intending to quit smoking with current and accurate e-cigarette information. Findings may inform future Stop Smoking Services provision and the results demonstrate that further research is warranted.

Lung cancer among coal miners, ore miners and quarrymen : smoking-adjusted risk estimates from the synergy pooled analysis of case-control studies

OBJECTIVES Working in mines and quarries has been associated with an elevated lung cancer risk but with inconsistent results for coal miners. This study aimed to estimate the smoking-adjusted lung cancer risk among coal miners and compare the risk pattern with lung cancer risks among ore miners and quarrymen. METHODS We estimated lung cancer risks of coal and ore miners and quarrymen among 14 251 lung cancer cases and 17 267 controls from the SYNERGY pooled case-control study, controlling for smoking and employment in other at-risk occupations. RESULTS Ever working as miner or quarryman (690 cases, 436 controls) was associated with an elevated odds ratio (OR) of 1.55 [95% confidence interval (95% CI) 1.34-1.79] for lung cancer. Ore miners (53 cases, 24 controls) had a higher OR (2.34, 95% CI 1.36-4.03) than quarrymen (67 cases, 39 controls; OR 1.92, 95% CI 1.21-3.05) and coal miners (442 cases, 297 controls; OR 1.40, 95% CI 1.18-1.67), but CI overlapped. We did not observe trends by duration of exposure or time since last exposure. CONCLUSIONS This pooled analysis of population-based studies demonstrated an excess lung cancer risk among miners and quarrymen that remained increased after adjustment for detailed smoking history and working in other at-risk occupations. The increase in risk among coal miners were less pronounced than for ore miners or quarrymen.