Long non-coding RNA dysregulation is a frequent event in non-small cell lung carcinoma pathogenesis.

BACKGROUND: Long non-coding RNAs compose an important level of epigenetic regulation in normal physiology and disease. Despite the plethora of publications of lncRNAs in human cancer, the landscape is still unclear. METHODS: Microarray analysis in 44 NSCLC paired specimens was followed by qPCR-based validation in 29 (technical) and 38 (independent) tissue pairs. Cross-validation of the selected targets was achieved in 850 NSCLC tumours from TCGA datasets. RESULTS: Twelve targets were successfully validated by qPCR (upregulated: FEZF1-AS1, LINC01214, LINC00673, PCAT6, NUTM2A-AS1, LINC01929; downregulated: PCAT19, FENDRR, SVIL-AS1, LANCL1-AS1, ADAMTS9-AS2 and LINC00968). All of them were successfully cross validated in the TCGA datasets. Abnormal DNA methylation was observed in the promoters of FENDRR, FEZF1-AS1 and SVIL-AS1. FEZF1-AS1 and LINC01929 were associated with survival in the TCGA set. CONCLUSIONS: Our study provides through multiple levels of internal and external validation, a comprehensive list of dysregulated lncRNAs in NSCLC. We therefore envisage this dataset to serve as an important source for the lung cancer research community assisting future investigations on the involvement of lncRNAs in the pathogenesis of the disease and providing novel biomarkers for diagnosis, prognosis and therapeutic stratification.

Evaluation of a health service adopting proactive approach to reduce high risk of lung cancer: The Liverpool Healthy Lung Programme.

OBJECTIVES: This Liverpool Healthy Lung Programme is a response to high rates of lung cancer and respiratory diseases locally and aims to diagnose lung cancer at an earlier stage by proactive approach to those at high risk of lung cancer. The objective of this study is to evaluate the programme in terms of its likely effect on mortality from lung cancer and its delivery to deprived populations. METHODS: Persons aged 58-75 years, with a history of smoking or a diagnosis of chronic obstructive pulmonary disease (COPD)2 according to general practice records were invited for lung health check in a community health hub setting. A detailed risk assessment and spirometry were performed in eligible patients. Those with a 5% or greater five-year risk of lung cancer were referred for a low dose CT3 scan. RESULTS: A total of 4 566 subjects attended the appointment for risk assessment and 3 591 (79%) consented to data sharing. More than 80% of the patients were in the most deprived quintile of the index of multiple deprivation. Of those attending, 63% underwent spirometry and 43% were recommended for a CT scan. A total of 25 cancers were diagnosed, of which 16 (64%) were stage I. Comparison with the national stage distribution implied that the programme was reducing lung cancer mortality by 22%. CONCLUSIONS: Community based proactive approaches to early diagnosis of lung cancer in health deprived regions are likely to be effective in early detection of lung cancer.

DPP-4 Inhibitor Dose Selection According to Manufacturer Specifications: A Contemporary Experience From UK General Practice.

Recently, 2 dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin and saxagliptin, adjusted dosing specification from creatinine clearance to glomerular filtration rate, more typically reported in routine laboratory tests. This cross-sectional study examines all DPP-4 inhibitor initiations that require dose adjustment and the dose selection using data from UK general practice. Results indicate that 34% of patients taking a nonlinagliptin DPP-4 inhibitor were given a higher dose and 11% a lower dose than specified in the Summary of Product Characteristics. This reinforces the deviation from Summary of Product Characteristics prescription of DPP-4 inhibitors identified in earlier studies despite improvement in compatibility with routine reporting.

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

Probability of cancer in lung nodules using sequential volumetric screening up to 12 months: the UKLS trial.

BACKGROUND: Estimation of the clinical probability of malignancy in patients with pulmonary nodules will facilitate early diagnosis, determine optimum patient management strategies and reduce overall costs. METHODS: Data from the UK Lung Cancer Screening trial were analysed. Multivariable logistic regression models were used to identify independent predictors and to develop a parsimonious model to estimate the probability of lung cancer in lung nodules detected at baseline and at 3-month and 12-month repeat screening. RESULTS: Of 1994 participants who underwent CT scan, 1013 participants had a total of 5063 lung nodules and 52 (2.6%) of the participants developed lung cancer during a median follow-up of 4 years. Covariates that predict lung cancer in our model included female gender, asthma, bronchitis, asbestos exposure, history of cancer, early and late onset of family history of lung cancer, smoking duration, FVC, nodule type (pure ground-glass and part-solid) and volume as measured by semiautomated volumetry. The final model incorporating all predictors had excellent discrimination: area under the receiver operating characteristic curve (AUC 0.885, 95% CI 0.880 to 0.889). Internal validation suggested that the model will discriminate well when applied to new data (optimism-corrected AUC 0.882, 95% CI 0.848 to 0.907). The risk model had a good calibration (goodness-of-fit χ[8] 8.13, p=0.42). CONCLUSIONS: Our model may be used in estimating the probability of lung cancer in nodules detected at baseline and at 3 months and 12 months from baseline, allowing more efficient stratification of follow-up in population-based lung cancer screening programmes. TRIAL REGISTRATION NUMBER: 78513845.

Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis.

BACKGROUND: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. METHODS: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. RESULTS: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. CONCLUSIONS: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. IMPACT: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

Utilizing Lung Cancer Risk Prediction Models to Promote Smoking Cessation: Two Randomized Controlled Trials.

PURPOSE: The current project sought to examine whether delivery of lung cancer risk projections (calculated using the Liverpool Lung Project [LLP] risk model) predicted follow-up smoking status. DESIGN: Two single-blinded randomized controlled trials. SETTING: Stop Smoking Services in Liverpool (United Kingdom). PARTICIPANTS: Baseline current smokers (N = 297) and baseline recent former smokers (N = 216) were recruited. INTERVENTION: Participants allocated to intervention groups were provided with personalized lung cancer risk projections, calculated using the LLP risk model. MEASURES: Baseline and follow-up questionnaires explored sociodemographics, smoking behavior, and lung cancer risk perceptions. ANALYSIS: Bivariate analyses identified significant differences between randomization groups, and logistic regression models were developed to investigate the intervention effect on the outcome variables. RESULTS: Lung cancer risk projections were not found to predict follow-up smoking status in the trial of baseline current smokers; however, they did predict follow-up smoking status in the trial of baseline recent former smokers (odds ratio: 1.91; 95% confidence interval: 1.03-3.55). CONCLUSION: The current study suggests that lung cancer risk projections may help maintain abstinence among individuals who have quit smoking, but the results did not provide evidence to suggest that lung cancer risk projections motivate current smokers to quit.

Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium.

Purpose: DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients.Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan-Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage.Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08-1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84-1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61-1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190.Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors. Clin Cancer Res; 23(24); 7550-7. ©2017 AACR.

Age at menopause and hormone replacement therapy as risk factors for head and neck and oesophageal cancer (Review).

There were ~986,000 cases of head and neck cancer (HNC) and oesophageal cancer diagnosed worldwide in 2012. The incidence of these types of cancer is much higher in males than females, although this disparity decreases in the elderly population, suggesting a role for hormones as a risk factor. This systematic review investigates the potential role of female hormones [age at menopause and use of hormone replacement therapy (HRT)] as risk factors for HNC/oesophageal squamous cell carcinoma (SCC). The electronic databases MEDLINE, Web of Science, EMBASE and Cochrane were searched. Only studies with at least 50 cases of HNC/oesophageal SCC, with data on age at menopause, smoking, alcohol, age and socioeconomic status or educational attainment, were included. The Newcastle Ottawa Scale was used for assessing risk of bias. Eight studies met the inclusion criteria (5 oesophageal SCC, 2 HNC and 1 combined oesophageal SCC and HNC). HRT was shown to reduce the risk of HNC (HR, 0.78; 95% CI, 0.61-0.99) in one study. Our results showed that earlier age at menopause is a risk factor for oesophageal SCC, with women entering menopause at <45 years having double the risk of those entering menopause at age >50 years. Similar, but less striking, results were observed for HNC. HRT was found to reduce the risk of HNC/oesophageal SCC, but the evidence is inconclusive. We, therefore, recommend that consideration should be given to collecting data on reproductive factors and exposure to HRT, as routine practice, in future epidemiological and clinical studies of these cancers. The concept of oestrogen deficiency as a risk for HNC/oesophageal SCC deserves further exploration in future laboratory and clinical studies.

AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer.

Deregulation of mitotic spindle genes has been reported to contribute to the development and progression of malignant tumours. The aim of the present study was to explore the association between the expression profiles of Aurora kinases (AURKA, AURKB and AURKC), cytoskeleton-associated protein 5 (CKAP5), discs large-associated protein 5 (DLGAP5), kinesin-like protein 11 (KIF11), microtubule nucleation factor (TPX2), monopolar spindle 1 kinase (TTK), and ß-tubulins (TUBB) and (TUBB3) genes and clinicopathological characteristics in human non-small cell lung carcinoma (NSCLC). Reverse transcription-quantitative polymerase chain reaction-based RNA gene expression profiles of 132 NSCLC and 44 adjacent wild-type tissues were generated, and Cox's proportional hazard regression was used to examine associations. With the exception of AURKC, all genes exhibited increased expression in NSCLC tissues. Of the 10 genes examined, only AURKA was significantly associated with prognosis in NSCLC. Multivariate Cox's regression analysis demonstrated that AURKA mRNA expression [hazard ratio (HR), 1.81; 95% confidence interval (CI), 1.16-2.84; P=0.009], age (HR, 1.03; 95% CI, 1.00-1.06; P=0.020), pathological tumour stage 2 (HR, 2.43; 95% CI, 1.16-5.10; P=0.019) and involvement of distal nodes (pathological node stage 2) (HR, 3.14; 95% CI, 1.24-7.99; P=0.016) were independent predictors of poor prognosis in patients with NSCLC. Poor prognosis of patients with increased AURKA expression suggests that those patients may benefit from surrogate therapy with AURKA inhibitors.

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.

Risk assessment in relation to the detection of small pulmonary nodules.

The National Lung Cancer Screening trial (NLST) demonstrated that individuals assigned to the LDCT screening arm had a 20% lower mortality than those who were assigned to the conventional chest radiography. The NLST was thoroughly analyzed by the US Preventive Task Force on CT Screening and they recommended that lung cancer screening should be implemented. A number of other countries have also recommended implementation, whilst others are awaiting the outcome of the NELSON Trial. However, recommendations for the management of CT screen detected nodules have only recently had any clarity. The management of CT detected nodules in the NLST was based on the identification and reporting of 4 mm diameter nodules found on the CT screens but there was no NLST radiology protocol in place for the management of nodules. The use of volumetric analysis is not routinely used in the USA and there is still a reliance on utilising the CT nodule diameter as the management parameter. The first pulmonary risk model was developed by the Canadians, utilising data sets from the Pan-Canadian Early detection of Lung cancer (PanCan) and validated in the chemoprevention trial dataset at the British Columbian Agency. This Canadian model, known as the Brock Model, is currently available and has been integrated into the British Thoracic Society guidelines on the management of pulmonary nodules. The American College of Radiology setup a Lung Cancer Screening Committee subgroup on Lung-RADS, to standardize lung cancer screening CT reporting and provide management recommendations. However, it has been recommended that the Lung-RADS system should be revised as the system as it has never been studied in a prospective fashion. The NELSON trial introduced a third screening test, the "indeterminate" screening test result, this was done with the aim to reduce the false-positives CT screening results and also utilized by the UKLS trial successfully. On comparing the radiological CT screen volumetric and diameter based protocols in the NELSON trial, the sensitivity and negative predictive value appeared to be comparable, however a higher specificity and positive predictive value was found for the volume-based protocols, thus confirming the advantage of utilising the volumetric approach over diameter The British Thoracic Society (BTS) has undertaken an in-depth piece of work developing guidelines on the management of pulmonary nodules, utilising the wealth of data published by the NELSON team and support the use of volumetric analysis for the management of pulmonary nodules.

Aurora B expression modulates paclitaxel response in non-small cell lung cancer.

BACKGROUND: Taxanes are mitotic poisons widely used in the treatment of non-small cell lung cancer (NSCLC), however, little is known about potential molecular modulators of response to these compounds. Aurora B (AURKB) is a critical regulator of the mitotic spindle assembly, previously shown overexpressed in NSCLC. Here we investigated the hypothesis that AURKB expression modulates the efficacy of taxanes in NSCLC cells. METHODS: AURKB mRNA expression was determined by qPCR in 132 frozen NSCLC tissues and nine NSCLC cell lines. Aurora B expression was knocked down in cell lines using multiple shRNA constructs. Barasertib was used to specifically inhibit AURKB activity, determined by the level of H3S10 phosphorylation. RESULTS: Frequent AURKB mRNA upregulation was observed in NSCLC tissues (P<0.0001), being more prominent in squamous carcinomas (P<0.0001). Aurora B expression in cell lines strongly correlated with sensitivity to both docetaxel (P=0.004) and paclitaxel (P=0.007). Aurora B knockdown derivatives consistently showed a dose-dependent association between low-AURKB expression and resistance to paclitaxel. Specific chemical inhibition of Aurora B activity also demonstrated a strong dose-dependent efficiency in triggering paclitaxel resistance. CONCLUSIONS: Aurora B activity is an important modulator of taxane response in NSCLC cells. This may lead to further insights into taxane sensitivity of NSCLC tumours.

Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model.

Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs. Multivariable logistic regression was used to identify similar risk predictors for lung cancer in the LLP risk model for the epidemiological model and extended model with SNPs. Both models were internally validated using the bootstrap method and model performance was assessed using area under the curve (AUC) and net reclassification improvement (NRI). Using MDR and RF, the overall best classifier of lung cancer status were SNPs rs1799732 (DRD2), rs5744256 (IL-18), rs2306022 (ITGA11) with training accuracy of 0.6592 and a testing accuracy of 0.6572 and a cross-validation consistency of 10/10 with permutation testing P<0.0001. The apparent AUC of the epidemiological model was 0.75 (95% CI 0.73-0.77). When epistatic data were incorporated in the extended model, the AUC increased to 0.81 (95% CI 0.79-0.83) which corresponds to 8% increase in AUC (DeLong's test P=2.2e-16); 17.5% by NRI. After correction for optimism, the AUC was 0.73 for the epidemiological model and 0.79 for the extended model. Our results showed modest improvement in lung cancer risk prediction when the SNP epistasis factor was added.

Perceptions towards electronic cigarettes for smoking cessation among Stop Smoking Service users.

OBJECTIVES: Electronic cigarettes (e-cigarettes) are promoted as smoking cessation tools, yet they remain unavailable from Stop Smoking Services in England; the debate over their safety and efficacy is ongoing. This study was designed to explore perceptions and reasons for use or non-use of electronic cigarettes as smoking cessation tools, among individuals engaged in Stop Smoking Services. METHODS: Semi-structured telephone interviews were undertaken with twenty participants engaged in Stop Smoking Services in the north-west of England. Participants comprised of both individuals who had tried e-cigarettes (n = 6) and those who had not (n = 14). Interviews were digitally recorded and transcribed verbatim. The transcripts were subject to thematic analysis, which explored participants' beliefs and experiences of e-cigarettes. RESULTS: A thematic analysis of transcripts suggested that the following three superordinate themes were prominent: (1) self-efficacy and beliefs in e-cigarettes; (2) e-cigarettes as a smoking cessation aid; and (3) cues for e-cigarette use. Participants, particularly never users, were especially concerned regarding e-cigarette efficacy and safety. Overall, participants largely expressed uncertainty regarding e-cigarette safety and efficacy, with some evidence of misunderstanding. CONCLUSIONS: Evidence of uncertainty and misunderstanding regarding information on e-cigarettes highlights the importance of providing smokers with concise, up-to-date information regarding e-cigarettes, enabling smokers to make informed treatment decisions. Furthermore, identification of potential predictors of e-cigarette use can be used to inform Stop Smoking Services provision and future research. STATEMENT OF CONTRIBUTION: What is already known on this subject? Research suggests that e-cigarettes may help smokers quit smoking, but further studies are needed. Electronic cigarette use in Stop Smoking Services has increased substantially in recent years, although e-cigarettes are currently not regulated. There is debate within the academic community regarding e-cigarette efficacy and safety. What does this study add? Service users interviewed in the current study felt uncertain regarding e-cigarette efficacy and safety. E-cigarette ever users viewed e-cigarettes as effective and safe, more often than never users. Accurate and up-to-date education will enable service users to make informed treatment decisions.

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.