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Background: Radon is a radioactive gas and a major risk factor for lung cancer (LC)., Methods: We investigated the dose-response relationship between radon and LC risk in the International Lung Cancer Consortium with 8927 cases and 5562 controls from Europe, North America, and Israel, conducted between 1992 and 2016. Spatial indoor radon exposure in the residential area (sIR) obtained from national surveys was linked to the participants' residential geolocation. Parametric linear and spline functions were fitted within a logistic regression framework., Results: We observed a non-linear spatial-dose response relationship for sIR < 200 Bq/m 3 . The lowest risk was observed for areas of mean exposure of 58 Bq/m 3 (95% CI: 56.1-59.2 Bq/m 3 ). The relative risk of lung cancer increased to the same degree in areas averaging 25 Bq/m 3 (OR = 1.31, 95% CI: 1.01-1.59) as in areas with a mean of 100 Bq/m 3 (OR = 1.34, 95% CI: 1.20-1.45). The strongest association was observed for small cell lung cancer and the weakest for squamous cell carcinoma. A stronger association was also observed in men, but only at higher exposure levels. The non-linear association is primarily observed among the younger population (age < 69 years), but not in the older population, which can potentially represent different biological radiation responses., Conclusions: The sIR is useful as proxy of individual radon exposure in epidemiological studies on lung cancer. The usual assumption of a linear, no-threshold dose-response relationship, as can be made for individual radon exposures, may not be optimal for sIR values of less than 200 Bq/m 3 ., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer., Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer., Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10 -16 ), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10 -16 ), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10 -14 ). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate., Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease., (Copyright © 2019 International Association for the Study of Lung Cancer. All rights reserved.)

Rationale: Previous respiratory diseases have been associated with increased risk of lung cancer. Respiratory conditions often co-occur and few studies have investigated multiple conditions simultaneously., Objectives: Investigate lung cancer risk associated with chronic bronchitis, emphysema, tuberculosis, pneumonia, and asthma., Methods: The SYNERGY project pooled information on previous respiratory diseases from 12,739 case subjects and 14,945 control subjects from 7 case-control studies conducted in Europe and Canada. Multivariate logistic regression models were used to investigate the relationship between individual diseases adjusting for co-occurring conditions, and patterns of respiratory disease diagnoses and lung cancer. Analyses were stratified by sex, and adjusted for age, center, ever-employed in a high-risk occupation, education, smoking status, cigarette pack-years, and time since quitting smoking., Measurements and Main Results: Chronic bronchitis and emphysema were positively associated with lung cancer, after accounting for other respiratory diseases and smoking (e.g., in men: odds ratio [OR], 1.33; 95% confidence interval [CI], 1.20-1.48 and OR, 1.50; 95% CI, 1.21-1.87, respectively). A positive relationship was observed between lung cancer and pneumonia diagnosed 2 years or less before lung cancer (OR, 3.31; 95% CI, 2.33-4.70 for men), but not longer. Co-occurrence of chronic bronchitis and emphysema and/or pneumonia had a stronger positive association with lung cancer than chronic bronchitis "only." Asthma had an inverse association with lung cancer, the association being stronger with an asthma diagnosis 5 years or more before lung cancer compared with shorter., Conclusions: Findings from this large international case-control consortium indicate that after accounting for co-occurring respiratory diseases, chronic bronchitis and emphysema continue to have a positive association with lung cancer.

The indiscriminate use of the cumulative exposure metric (the product of intensity and duration of exposure) might bias reported associations between exposure to hazardous agents and cancer risk. To assess the independent effects of duration and intensity of exposure on cancer risk, we explored effect modification of the association of cumulative exposure and cancer risk by intensity of exposure. We applied a flexible excess odds ratio model that is linear in cumulative exposure but potentially nonlinear in intensity of exposure to 15 case-control studies of cigarette smoking and lung cancer (1985-2009). Our model accommodated modification of the excess odds ratio per pack-year of cigarette smoking by time since smoking cessation among former smokers. We observed negative effect modification of the association of pack-years of cigarette smoking and lung cancer by intensity of cigarette smoke for persons who smoked more than 20-30 cigarettes per day. Patterns of effect modification were similar across individual studies and across major lung cancer subtypes. We observed strong negative effect modification by time since smoking cessation. Application of our method in this example of cigarette smoking and lung cancer demonstrated that reducing a complex exposure history to a metric such as cumulative exposure is too restrictive.

Purpose: Antiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non-small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC)., Patients and Methods: We evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC., Results: The combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC., Conclusion: Our results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC.

Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.

Because aggregation of cancers at different sites can occur in families, cancer could be considered as a broad phenotype with shared genetic factors. Here, we report results from a multi-centre case-control study of non-small cell lung cancer (NSCLC), with particular emphasis on a history of cancer in first-degree relatives and the risk of lung cancer. From 2002 to 2006, 733 NSCLC patients treated surgically were recruited in 8 European countries and matched to 1312 controls, by centre, sex and age. We used multivariate conditional logistic regression models to test the association between a history of cancer in first-degree relatives and risk of NSCLC. A family history of lung cancer was associated with an odds ratio (OR) for early-onset (54 years or younger) NSCLC of 4.72 (95% confidence interval [CI]=1.02-21.90). A family history of gastric cancer was associated with an OR for NSCLC of 1.82 (95% CI=1.08-3.06) and for late-onset (55 years or older) NSCLC of 2.92 (95% CI=1.10-7.75). Our findings provide further evidence of a familial predisposition to lung cancer and support the hypothesis that family history is a significant risk factor for the disease. Because of the inherent potential for bias in familial case-control study design, cautious interpretation is warranted.

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

Background: The role of crystalline silica dust as a possible cause of lung cancer has been controversial. Relatively few large community-based studies have been conducted to investigate the lung cancer risk from exposure to silica at low levels, taking into account potential confounding factors., Methods: Detailed lifestyle and occupational information were collected from 2852 newly diagnosed cases of lung cancer and 3104 controls between 1998 and 2002 in 7 European countries. For each job held, local experts assessed the probability, intensity, and duration of silica exposure., Results: Occupational exposure to crystalline silica was associated with an increased risk of lung cancer (odds ratio = 1.37; 95% confidence interval = 1.14-1.65). This risk was most apparent for the upper tertile of cumulative exposure (OR = 2.08; 95% CI = 1.49-2.90; P for trend <0.0001), duration of exposure (1.73; 1.26-2.39; P for trend = 0.0001) and weighted duration of exposure (1.88; 1.35-2.61; P for trend <0.0001). We did not observe any interaction beyond a multiplicative model between tobacco smoking and silica exposure., Conclusions: Our results support the hypothesis that silica is an important risk factor for lung cancer. This risk could not be explained by exposure to other occupational carcinogens or smoking, and it was present for the main histologic types of lung cancer, different sources of silica exposure, and different industrial settings.