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Dietary factors are assumed to play an important role in cancer risk, apparent in consensus recommendations for cancer prevention that promote nutritional changes. However, the evidence in this field has been generated predominantly through observational studies, which may result in biased effect estimates because of confounding, exposure misclassification, and reverse causality. With major geographical differences and rapid changes in cancer incidence over time, it is crucial to establish which of the observational associations reflect causality and to identify novel risk factors as these may be modified to prevent the onset of cancer and reduce its progression. Mendelian randomization (MR) uses the special properties of germline genetic variation to strengthen causal inference regarding potentially modifiable exposures and disease risk. MR can be implemented through instrumental variable (IV) analysis and, when robustly performed, is generally less prone to confounding, reverse causation and measurement error than conventional observational methods and has different sources of bias (discussed in detail below). It is increasingly used to facilitate causal inference in epidemiology and provides an opportunity to explore the effects of nutritional exposures on cancer incidence and progression in a cost-effective and timely manner. Here, we introduce the concept of MR and discuss its current application in understanding the impact of nutritional factors (e.g., any measure of diet and nutritional intake, circulating biomarkers, patterns, preference or behaviour) on cancer aetiology and, thus, opportunities for MR to contribute to the development of nutritional recommendations and policies for cancer prevention. We provide applied examples of MR studies examining the role of nutritional factors in cancer to illustrate how this method can be used to help prioritise or deprioritise the evaluation of specific nutritional factors as intervention targets in randomised controlled trials. We describe possible biases when using MR, and methodological developments aimed at investigating and potentially overcoming these biases when present. Lastly, we consider the use of MR in identifying causally relevant nutritional risk factors for various cancers in different regions across the world, given notable geographical differences in some cancers. We also discuss how MR results could be translated into further research and policy. We conclude that findings from MR studies, which corroborate those from other well-conducted studies with different and orthogonal biases, are poised to substantially improve our understanding of nutritional influences on cancer. For such corroboration, there is a requirement for an interdisciplinary and collaborative approach to investigate risk factors for cancer incidence and progression.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40–80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was − 0.91 standard-deviations lower in women than men (95%CI − 0.98; − 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p

Background It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development. Methods We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009–13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995–97) and HUNT3 (2006–08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer. Results The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P Conclusions DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer–related dysregulation of CDCP1 expression years before diagnosis. Significance: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms. See related commentary by Itzstein et al., p. 3441.

Systemic inflammation markers have been linked to increased cancer risk and mortality in a number of studies. However, few studies have estimated pre-diagnostic associations of systemic inflammation markers and cancer risk. Such markers could serve as biomarkers of cancer risk and aid in earlier identification of the disease. This study estimated associations between pre-diagnostic systemic inflammation markers and cancer risk in the prospective UK Biobank cohort of approximately 440,000 participants recruited between 2006 and 2010. We assessed associations between four immune-related markers based on blood cell counts: systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and risk for 17 cancer sites by estimating hazard ratios (HR) using flexible parametric survival models. We observed positive associations with risk for seven out of 17 cancers with SII, NLR, PLR, and negative associations with LMR. The strongest associations were observed for SII for colorectal and lung cancer risk, with associations increasing in magnitude for cases diagnosed within one year of recruitment. For instance, the HR for colorectal cancer per standard deviation increment in SII was estimated at 1.09 (95% CI 1.02–1.16) in blood drawn five years prior to diagnosis and 1.50 (95% CI 1.24–1.80) in blood drawn one month prior to diagnosis. We observed associations between systemic inflammation markers and risk for several cancers. The increase in risk the last year prior to diagnosis may reflect a systemic immune response to an already present, yet clinically undetected cancer. Blood cell ratios could serve as biomarkers of cancer incidence risk with potential for early identification of disease in the last year prior to clinical diagnosis. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00752-6.

Although smoking and oxidative stress are known contributors to lung carcinogenesis, their mechanisms of action remain poorly understood. To shed light into these mechanisms, we applied a novel approach using Cys34-adductomics in a lung cancer nested case-control study (n = 212). Adductomics profiles were integrated with DNA-methylation data at established smoking-related CpG sites measured in the same individuals. Our analysis identified 42 Cys34-albumin adducts, of which 2 were significantly differentially abundant in cases and controls: adduct of N-acetylcysteine (NAC, p = 4.15 × 10-3 ) and of cysteinyl-glycine (p = 7.89 × 10-3 ). Blood levels of the former were found associated to the methylation levels at 11 smoking-related CpG sites. We detect, for the first time in prospective blood samples, and irrespective of time to diagnosis, decreased levels of NAC adduct in lung cancer cases. Altogether, our results highlight the potential role of these adducts in the oxidative stress response contributing to lung carcinogenesis years before diagnosis.

ObjectivesIn a previous analysis of data from a French population-based case–control study (the Investigation of occupational and environmental CAuses of REspiratory cancers (ICARE) study), ‘having ever worked’ in wood-related occupations was associated with excess lung cancer risk after adjusting for smoking but not for occupational factors. The present study aimed to investigate the relationship between lung cancer risk and wood dust exposure after adjusting for occupational exposures.MethodsData were obtained from 2276 cases and 2780 controls on smoking habits and lifelong occupational history, using a standardised questionnaire with a job-specific questionnaire for wood dust exposure. Logistic regression models were used to calculate ORs and 95% CIs adjusted for age, area of residence, tobacco smoking, the number of job periods and exposure to silica, asbestos and diesel motor exhaust (DME).ResultsNo significant association was found between lung cancer and wood dust exposure after adjustment for smoking, asbestos, silica and DME exposures. The risk of lung cancer was slightly increased among those who were exposed to wood dust more than 10 years, and had over 40 years since the first exposure.ConclusionOur findings do not provide a strong support to the hypothesis that wood dust exposure is a risk factor for lung cancer. This study showed the importance of taking into account smoking and occupational coexposures in studies on lung cancer and wood dust exposure. Further studies evaluating the level and frequency of exposure during various tasks in woodwork are needed.

DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-valuepooled = 4 × 10-17 ), cg03636183 in the F2RL3 gene (p-valuepooled = 2 × 10 - 13 ), cg21566642 and cg05951221 in 2q37.1 (p-valuepooled = 7 × 10-16 and 1 × 10-11 respectively), cg06126421 in 6p21.33 (p-valuepooled = 2 × 10-15 ) and cg23387569 in 12q14.1 (p-valuepooled = 5 × 10-7 ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-valuesheterogeneity ≤ 1.8 x10 - 7 ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.

IMPORTANCE: There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases. OBJECTIVE: To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria. DESIGN, SETTING, AND PARTICIPANTS: Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS). MAIN OUTCOMES AND MEASURES: Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver-operating characteristics curve [AUC], sensitivity, and specificity). RESULTS: In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (P = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model. CONCLUSIONS AND RELEVANCE: This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening.

Background Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine—a nicotine metabolite and biomarker of recent tobacco exposure—provides additional information on lung cancer risk. Methods The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis. Results We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32–1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68–0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64–0.68) (P = 1.5x10–9). Conclusions Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone. © The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

International audience; Background - To investigate the association of lung cancer with occupational exposure to textile dust and specifically to cotton dust in the population-based case-control study ICARE. Methods - Lifelong occupational history of 2926 cases and 3555 controls was collected using standardized questionnaires, with specific questions for textile dust exposure. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models controlling for confounding factors including smoking and asbestos exposure. Results - An inverse association between textile dust exposure and lung cancer was found among workers exposed ≥5% of their work time (OR = 0.80, 95%CI = 0.58-1.09), more pronounced for distant exposures (40+ years; up to a 56% reduced risk, statistically significant). The OR of lung cancer was significantly decreased among workers exposed to cotton fibers (OR = 0.70, 95%CI = 0.48-0.97). Conclusions - Our results provide some evidence of a decreased risk of lung cancer associated with exposure to textile dust, particularly cotton.

Purpose We investigated the role of occupational exposure to endotoxin in lung cancer risk in a French population based case-control study. Methods Lifelong work histories of 2926 cases and 3555 controls were collected using standardised questionnaires. Estimation of endotoxin exposure was based on a publication issued by the Institut National de Recherche et de Securite (INRS), which reported measurements in biological aerosols workstations. Several exposure-related variables were created: intensity ( 1000UE/m³), total duration (years), life time cumulative exposure (UE/m³*years) and time since cessation (years). Smoking history was combined into a comprehensive smoking index (CSI) that included mean number of cigarettes/day, duration and time since cessation. Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression models and controlled for main confounding factors including CSI. Results We found an inverse significant association between high endotoxin exposure and lung cancer risk (151 cases/336 controls; OR = 0.64, 95% Cl = 0.5–0.82). The main activity sectors entailing high exposure included dairy, cattle, poultry and pig farms. In contrast, a statistically significant positive association was found for low exposure (OR = 1.33, 95% Cl = 1.08–1.64) (eg. sawmills, wool industry, meat processing). Using restricted splines cubic models, we observed that the association between cumulative endotoxin exposures and lung cancer risk departed significantly from linearity. In addition, the risk decreased with duration and increased with time since cessation, irrespective of the exposure intensity. Analysis by subgroups showed an interaction with tobacco consumption, and light smokers appeared to be more sensitive to endotoxin protective effect. Conclusions Our findings suggest that high exposure to endotoxin confers protection against lung cancer.

Background Few occupational studies have addressed head and neck cancer, and these studies have been predominantly conducted in men. Accordingly, our objective was to investigate the association between head and neck cancer and occupation in women. Methods ICARE, a French population-based case–control study, included 296 squamous cell carcinomas of the head and neck in women and 775 controls. Lifelong occupational history was collected. Odds ratios (ORs) and 95% confidence intervals (CI), adjusted for smoking, alcohol drinking and education level, were estimated for occupations and industries. Results An elevated OR was observed for working proprietors working for 10 years or more (OR = 3.83, 95% CI: 1.12–13.0) with a significant trend with duration of employment (P = 0.047). Elevated but non-significant ORs were observed for street vendors (OR = 3.76, 95% CI: 0.99–14.3, P for trend = 0.13), bakers (OR = 4.19, 95% CI: 0.63–27.9, P for trend = 0.06), and welders and flame cutters (OR = 2.18, 95% CI: 0.33–14.4, P for trend = 0.05). Conclusions This exploratory study suggests a role of occupational exposures in the development of HN cancer in women. Further investigations of exposures to specific agents are needed. Am. J. Ind. Med. 57:1386–1397, 2014. © 2014 Wiley Periodicals, Inc.

International audience; OBJECTIVE: To investigate the role of occupational exposure to chlorinated solvents in lung cancer aetiology. METHODS: ICARE (Investigation of occupational and environmental CAuses of REspiratory cancers) is a French, multicentre, population-based, case-control study. Information on the lifelong work history of 2926 cases and 3555 controls was collected using standardised questionnaires. Occupational exposures were assessed using job-exposure matrices for five chlorinated solvents. Solvents were studied separately and in combinations. ORs were computed using unconditional logistic regression models adjusted for classic risk factors, including a history of cigarette smoking and exposure to asbestos. Adjustment for socioeconomic status (SES) was also made. RESULTS: After adjustment for exposure to asbestos, we observed a positive, statistically significant association with lung cancer for men and women exposed to a combination of perchloroethylene (PCE), trichloroethylene and dichloromethane (DCM). Further adjustment for SES slightly decreased this association. In contrast, no statistically significant associations were found for other solvent combinations. CONCLUSIONS: These results suggest that exposure to PCE may constitute a risk factor for lung cancer, especially among women, who seem to have a higher prevalence of exposure than men.

Background: Whether women are more or equally susceptible to the carcinogenic effects of cigarette smoke on the lungs compared with men is a matter of controversy. Using a large French population-based case–control study, we compared the lung cancer risk associated with cigarette smoking by gender. Methods: The study included 2276 male and 650 female cases and 2780 male and 775 female controls. Lifetime smoking exposure was represented by the comprehensive smoking index (CSI), which combines the duration, intensity and time since cessation of smoking habits. The analysis was conducted among the ever smokers. All of the models were adjusted for age, department (a regional administrative unit), education and occupational exposures. Results: Overall, we found that the lung cancer risk was similar among men and women. However, we found that women had a two-fold greater risk associated with a one-unit increase in CSI than men of developing either small cell carcinoma (OR=15.9, 95% confidence interval (95% CI) 7.6, 33.3 and 6.6, 95% CI 5.1, 8.5, respectively; P

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 Author 2013.

OBJECTIVE To investigate the associations between occupations and head and neck (HN) cancer risk in men. METHODS ICARE is a French population-based case-control study on HN cancer. Analyses included 1833 cases and 2747 controls. Complete occupational history was collected. Odds ratios (ORs) were estimated for occupations and industries ever held and according to duration of employment. RESULTS Elevated ORs, increasing with duration of employment, were observed for several occupations, including cleaners (OR = 1.7; 95% confidence interval [CI], 1.0 to 2.8), launderers (OR = 6.8; CI, 1.3 to 34.4), firefighters (OR = 3.9; CI, 1.4 to 11.2), several agricultural occupations, welders (OR = 1.9; CI, 1.3 to 2.8), structural metal preparers and erectors (OR = 2.1; CI, 1.2 to 3.7), rubber workers (OR = 2.0; CI, 1.0 to 3.9), several construction occupations, and material-handling equipment operators (OR = 1.8; CI, 1.1 to 2.9). Analyses by industry corroborated these findings. CONCLUSIONS These results confirmed the role of occupational exposures in HN cancer.

Background Results on the relationship between coffee and tea drinking and the risk of oral cavity cancer are contrasted. The aim of this study was to evaluate the relation between coffee and tea drinking and the risk of oral cavity cancer in France, a high incidence area. Material and methods We conducted a population based case–control study with face-to-face interviews and standardized questionnaires (the ICARE study, Investigation of occupational and environmental causes of respiratory cancers). We used data from 689 cases of oral cavity squamous cell carcinoma and 3481 controls. Odds-ratios (ORs) and 95% confidence intervals (95% CI) associated with tea and coffee consumption (quantity, duration, cumulative consumption) were estimated by unconditional logistic regression with adjustment for age, gender, area of residence, education, body mass index, tobacco smoking and alcohol drinking. Results We observed inverse associations between oral cavity cancer and tea or coffee consumption (odds ratio, 0.39; 95% CI 0.21–0.70, for the highest quartile of tea consumption, and 0.60, 95% CI 0.34–1.05, for the highest quartile of coffee consumption). Exclusive tea or coffee consumption was associated with a reduced risk of oral cavity cancer and their joint effect was multiplicative. No differences in risk between men and women or between consumers of tobacco and alcohol and non-consumers were observed. The odds ratios related to the subsites usually included in the oropharynx (soft palate and base of the tongue) did not differ significantly from that observed for the other subsites of the oral cavity. Conclusions Tea and coffee drinking may decrease the risk of oral cavity cancer through antioxidant components which play a role in the repair of cellular damages. These findings need further investigation in prospective studies and the underlying mechanisms in humans remain to be clarified.

The association between body mass index (BMI) and the risk of oral cavity cancer, suggested by the few available studies, is controversial because of weight loss preceding cancer diagnosis and possible confounding by tobacco and alcohol consumption. The aim of this study was to evaluate in France, a high-incidence country, the association between the risk of oral cavity cancer and body mass index at interview, 2 years before the interview and at age 30, as well as BMI change. We used data from a population-based case–control study, the Investigation of occupational and environmental CAuses of REspiratory cancers study, with personal interviews and standardized questionnaires including 689 cases of oral cavity squamous cell carcinoma and 3,481 controls. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were estimated by unconditional logistic regression and were adjusted for gender, age, area of residence, education, tobacco smoking, and alcohol drinking. ORs were increased in underweight subjects at interview (OR 6.25, 95 % CI 3.74–10.45). No association with underweight 2 years before the interview and at age 30 was found. Overweight and obesity at interview, 2 years before the interview and at age 30 were associated with decreased ORs (ranging from 0.13 to 0.60). BMI gain greater than 5 % between age 30 and 2 years before the interview was inversely associated with oral cavity cancer (OR 0.42, 95 % CI 0.33–0.54). These associations were stronger in men, and in smokers and drinkers. These results add further support to the existence of a reduced risk of oral cavity cancer among overweight and obese people or among people who increased their BMI in adulthood. The underlying mechanisms remain to be clarified.

Objectives Firefighters are potentially exposed to a wide variety of chemical compounds during the course of their work and inhalation is considered to be the major source of exposure. A large number of human carcinogens have been detected in smoke at fires. The aim was to investigate the risk of lung cancer among firefighters, while controlling for smoking habits. Methods We used data from the SYNERGY project including pooled information on lifetime work histories and smoking habits for 14,748 male lung cancer cases and 17,543 controls from 14 case-control studies conducted in Europe, Canada, New Zealand and China. There were 190 men who had ever worked as a firefighter (based on ISCO-68), among them 86 cases and 104 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusted for study, age, smoking, and ever employment in an occupation with established lung cancer risk. Results We observed no increased risk of lung cancer in firefighters, neither before (OR = 1.03, 95% CI: 0.77–1.38) nor after (OR = 0.95, 95% CI: 0.68–1.32) adjustment for smoking and exposure to other occupational lung carcinogens. There was no evidence of a trend of increasing lung cancer risk with increasing duration of work as a firefighter (p = 0.58) and no significant heterogeneity in lung cancer risk among firefighters across the studies. None of the major histological subtypes of lung cancer was associated with work as a firefighter. Conclusions We found no evidence of an excess lung cancer risk related to occupational exposure as a firefighter, when lifetime history of tobacco smoking and exposure to other occupational lung carcinogens was taken into account.

Introduction Lung cancer is the first cause of death from cancer worldwide. Survival improvement is hampered by the lack of the lack of understanding of the molecular mechanisms driving lung carcin...

Copyright Article author (or their employer) 2016. Background The association between lung cancer and occupational exposure to organic solvents is discussed. Since different solvents are often used simultaneously, it is difficult to assess the role of individual substances. Objectives The present study is focused on an in depth investigation of the potential association between lung cancer risk and occupational exposure to a large group of organic solvents, taking into account the well known risk factors for lung cancer, tobacco smoking and occupational exposure to asbestos. Methods We analysed data from the Investigation of occupational and environmental causes of respiratory cancers (ICARE) study, a large French population-based case–control study, set up between 2001 and 2007. A total of 2276 male cases and 2780 male controls were interviewed, and long-life occupational history was collected. In order to overcome the analytical difficulties created by multiple correlated exposures, we carried out a novel type of analysis based on Bayesian profile regression. Results After analysis with conventional logistic regression methods, none of the 11 solvents examined were associated with lung cancer risk. Through a profile regression approach, we did not observe any significant association between solvent exposure and lung cancer. However, we identified clusters at high risk that are related to occupations known to be at risk of developing lung cancer, such as painters. Conclusions Organic solvents do not appear to be substantial contributors to the occupational risk of lung cancer for the occupations known to be at risk. Ms Joëlle Fevotte for designing occupational questionnaires; all members of the MatGéné working group from the Institut de Veille Sanitaire and, Ms Brigitte Dananché and Mr Gwenaël GR Leday for his support in performing statistical analyses

Lower socioeconomic position (SEP) has consistently been associated with poorer health. To explore potential biological embedding and the consequences of SEP experiences from early life to adulthood, we investigate how SEP indicators at different points across the life course may be related to a combination of 28 inflammation markers. Using blood-derived inflammation profiles measured by a multiplex array in 268 participants from the Italian component of the European Prospective Investigation into Cancer and Nutrition cohort, we evaluate the association between early life, young adulthood and later adulthood SEP with each inflammatory markers separately, or by combining them into an inflammatory score. We identified an increased inflammatory burden in participants whose father had a manual occupation, through increased plasma levels of CSF3 (G-CSF; β = 0.29; P = 0.002) and an increased inflammatory score (β = 1.96; P = 0.029). Social mobility was subsequently modelled by the interaction between father’s occupation and the highest household occupation, revealing a significant difference between “stable Non-manual” profiles over the life course versus “Manual to Non-manual” profiles (β = 2.38, P = 0.023). Low SEP in childhood is associated with modest increase in adult inflammatory burden; however, the analysis of social mobility suggests a stronger effect of an upward social mobility over the life course.

International audience; Objectives: Lung cancer risk associated with occupational cleaning activities has been investigated in the population-based case-control study ICARE. Methods: Occupational history was collected by standardized interviews. Jobs were first defined according to the International Standard Classification of Occupations (ISCO) codes and then categorized according to activity sectors. Adjusted odds ratios (ORs) were estimated by unconditional logistic regression, separately for women (619 cases and 760 controls) and men (2265 and 2780). Results: Thirty percent of women and 2.3% of men controls ever held a cleaner or care job. Women who worked as housemaids longer than 7 years showed an OR of 1.76 [95% confidence interval (95% CI) 1.09 to 2.87] with respect to controls. Women employed in domestic service sector for a long time had an OR of 2.06 (95% CI 1.15 to 3.66). Conclusion: We confirmed and redefined the association of lung cancer with occupational cleaning, which concerns a considerable proportion of women workers.

Introduction Renal cell carcinoma (RCC) contributes significantly to the global cancer burden, annually accounting for over 140,000 deaths worldwide. Several lifestyle risk factors have been strongly implicated in RCC aetiology, most notably obesity and hypertension, as well as other factors associated with the metabolic syndrome (MetS). While these factors appear to be implicated in RCC aetiology from an epidemiological point of view, the underlying causal pathways remain to be elucidated. Our aim was to identify metabolites associated with RCC risk in pre-diagnostic blood samples. Methods A targeted metabolomic platform based on liquid chromatography tandem mass spectrometry (LC-MS; AbsoluteIDQ™ p180 kit from BIOCRATES), was used to quantify 145 metabolites in pre-diagnostic blood samples from 634 RCC case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC), and 140 case-control pairs from the Melbourne Collaborative Cohort study (MCCS). After excluding metabolites with more than 20% samples below the limit of detection or quantification, 127 metabolites were analysed in relation to RCC risk using conditional logistic regression. Metabolites associated with the risk of RCC in EPIC, after correction for multiple testing, were evaluated in MCCS. Further adjustment for body mass index (BMI), waist-to-hip ratio, alcohol and smoking was performed. Results After multiple testing correction (P-value Conclusions Our study is the first to evaluate the association between metabolites measured in pre-diagnostic blood samples and risk of RCC. The results highlight glycerophospholipids as a group of metabolites that may be important in RCC aetiology, but their causal relevance remains to be confirmed.

There is an urgent need to improve lung cancer risk assessment as current screening criteria miss a large proportion of cases and result in a high rate of false positives on low-dose CT screening. A fixed effect meta-analyses of 4 epigenome-wide association studies of lung cancer revealed differential DNA methylation at 16 CpG sites (FDR Citation Format: Florence Guida, Therese H. Nøst, Caroline Relton, Paul Brennan, Torkjel M. Sandanger, Marc Chadeau-Hyam, Mattias Johansson. Lung cancer risk prediction using DNA methylation markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2209.

DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk., Smoking tobacco is known to alter DNA methylation. Here, the authors show that hypomethylation of smoke-related genes is associated with future increase in lung cancer risk.

Introduction Environmental exposure early in life leads to complex combinations of risk factors for diseases later in life. Biomolecules such as DNA and its methylation patterns have the potential ...

International audience; OBJECTIVES: We investigated the relationship between lung cancer and occupational exposure to welding activity in ICARE, a population-based case-control study. METHODS: Analyses were restricted to men (2276 cases, 2780 controls). Welding exposure was assessed through detailed questionnaires, including lifelong occupational history. ORs were computed using unconditional logistic regression, adjusted for lifelong cigarette smoking and occupational exposure to asbestos. RESULTS: Among the regular welders, welding was associated with a risk of lung cancer (OR=1.7, 95% CI 1.1 to 2.5), which increased with the duration (OR=2.0, 95% CI 1.0 to 3.9 when duration \textgreater10 years), and was maximum 10-20 years since last welding. The risk was more pronounced in case of gas welding (OR=2.0, 95% CI 1.2 to 3.3), when the workpiece was covered by paint, grease, or other substances (OR=2.0, 95% CI 1.2 to 3.4) and when it was cleaned with chemical substances before welding. No statistically significant increase in lung cancer risk was observed among occasional welders. CONCLUSIONS: Although these results should be confirmed, we showed that type of welding and mode of workpiece preparation are important determinants of the lung cancer risk in regular welders

International audience; Objective The objective of the study was to investigate the joint effect of occupational exposure to asbestos, and tobacco and alcohol consumption, on the risk of laryngeal cancer among men. Methods We used data from a large population-based case–control study conducted in France. We estimated two-way and three-way interactions between asbestos exposure (never vs ever exposed), tobacco consumption (\textless20 vs ≥20 pack-years) and alcohol consumption (\textless5 vs ≥5 drinks per day). The interaction on an additive scale was assessed by estimating the relative excess risk due to interaction (RERI) and the attributable proportion due to interaction, and the interaction on a multiplicative scale was assessed by estimating the multiplicative interaction parameter (ψ). Multiplicative interactions were also assessed using fractional polynomials for alcohol drinking, tobacco smoking and asbestos exposure. Results When compared with light-to-moderate smokers and drinkers never exposed to asbestos, the increase in laryngeal cancer risk was smallest among light-to-moderate drinkers and smokers exposed to asbestos (OR=2.23 (1.08 to 4.60)), and highest among heavy smokers and drinkers ever exposed to asbestos (OR=69.39 (35.54 to 135.5)). We found an additive joint effect between asbestos exposure and alcohol consumption (RERI=4.75 (−4.29 to 11.12)), whereas we observed a more than additive joint effect between asbestos exposure and tobacco consumption (RERI=8.50 (0.71 to 23.81)), as well as between asbestos exposure, and tobacco and alcohol consumption (RERI=26.57 (11.52 to 67.88)). However, our results did not suggest any interaction on a multiplicative scale. Conclusions Our results suggest that asbestos exposure, in combination with tobacco and alcohol exposure, accounted for a substantial number of laryngeal cancer cases. Our findings therefore highlight the need for prevention in activities, such as construction work, where exposure to asbestos-containing materials remains

Coffee is one of the most widely consumed beverages and a major dietary exposure in the world. In 2007, the World Cancer Research Fund (WCRF) and the American Institute of Cancer Research (AICR) concluded in its report that for the association between lung cancer with dietary exposures such as coffee intake, the data were either of too low quality, or too inconsistent or the number of studies were too few to allow conclusions to be reached [1]. A meta-analysis (2010) of 13 studies reported significant positive association between coffee consumption and lung cancer risk [2]. However, there may still be residual confounding due to smoking. We sought to examine the association between coffee consumption and lung cancer risk in a large French population-based case–control study, the ICARE study (Investigation of occupational and environmental causes of respiratory cancers). The large sample size of this study allowed us to assess the association by gender, smoking status and histological types of lung cancer. The study design, study population and data collection methods of ICARE study have been described in detail elsewhere [3]. In brief, ICARE study is a large multi-centre

Introduction Some studies have suggested increased lung cancer risks among bakers, however the results overall were inconsistent. The authors studied lung cancer risks among bakers and baking-related occupations in the SYNERGY pooled case–control database from 16 countries. Methods Occupation in a baking-related job was identified from the subjects’ job histories. ORs adjusted for log(age), study centre, smoking behaviour and ever employment in a job with known exposure to occupational lung carcinogens were calculated by unconditional logistic regression. Findings were stratified by sex, histological subtype of lung cancer and smoking status. Results 19 366 cases (15 606 men) and 23 670 control subjects (18 528 men) were included. 473 cases (415 men, 58 women) and 501 controls (437 men, 64 women) had ever worked in baking or a related job. We did not observe an increased risk for men in baking (OR 1.01; 95% CI 0.86 to 1.18). No linear trends were observed for duration of employment. Some results suggested increased lung cancer risks for women, for example, for working as a baker for >30 years and in never-smokers, but after exclusion of one study these increased risks disappeared. Discussion The findings from this study do not suggest increased lung cancer risks in baking-related professions.

Objectives To assess the risk of lung cancer associated with exposure to mineral wools (MWs), while taking into account smoking, asbestos, and crystalline silica exposures. Methods The analyses were restricted to men (1350 cases and 1912 controls). Lifelong occupational history was collected. MWs and asbestos exposures were assessed, using task-exposure matrices and silica exposure, a job-exposure matrix. Results We observed consistent not-significant increased risks of lung cancer of the same order of magnitude among workers exposed to high levels of MWs (odds ratio, 1.4; 95% confidence interval: 0.9 to 2.2; for highest quartile of the Cumulative Exposure Index). Conclusions These results do not allow to draw firm conclusion about a carcinogenic effect of MWs on the lung, but they cannot exclude it. Given the high number of potentially exposed workers, it will be necessary to replicate them in a future further removed from the asbestos ban.

Background The aim of this study was to evaluate the role of family history of cancer and personal history of other medical conditions in the aetiology of the oral cavity cancer in France. Methods We used data from 689 cases of oral cavity squamous cell carcinoma and 3481 controls included in a population-based case–control study, the ICARE study. Odds-ratios (ORs) associated with family history of cancer and personal medical conditions and their 95% confidence intervals (95% CI) were estimated by unconditional logistic regression and were adjusted for age, gender, area of residence, education, body mass index, tobacco smoking and alcohol drinking. Results Personal history of oral candidiasis was related to a significantly increased risk of oral cavity cancer (OR 5.0, 95% CI 2.1-12.1). History of head and neck cancers among the first-degree relatives was associated with an OR of 1.9 (95% CI 1.2-2.8). The risk increased with the number of first-degree relatives with head and neck cancer. Conclusion A family history of head and neck cancer is a marker of an increased risk of oral cavity cancer and should be taken into account to target prevention efforts and screening. Further studies are needed to clarify the association between oral cavity cancer and personal history of candidiasis.

Increased lung cancer risks among hairdressers were observed in large registry-based cohort studies from Scandinavia, but these studies could not adjust for smoking. Our objective was to evaluate the lung cancer risk among hairdressers while adjusting for smoking and other confounders in a pooled database of 16 case-control studies conducted in Europe, Canada, China, and New Zealand between 1985 and 2010 (the Pooled Analysis of Case-Control Studies on the Joint Effects of Occupational Carcinogens in the Development of Lung Cancer). Lifetime occupational and smoking information was collected through interviews with 19,369 cases of lung cancer and 23,674 matched population or hospital controls. Overall, 170 cases and 167 controls had ever worked as hairdresser or barber. The odds ratios for lung cancer in women were 1.65 (95% confidence interval (CI): 1.16, 2.35) without adjustment for smoking and 1.12 (95% CI: 0.75, 1.68) with adjustment for smoking; however, women employed before 1954 also experienced an increased lung cancer risk after adjustment for smoking (odds ratio = 2.66, 95% CI: 1.09, 6.47). The odds ratios in male hairdressers/barbers were generally not elevated, except for an increased odds ratio for adenocarcinoma in long-term barbers (odds ratio = 2.20, 95% CI: 1.02, 4.77). Our results suggest that the increased lung cancer risks among hairdressers are due to their smoking behavior; single elevated risk estimates should be interpreted with caution and need replication in other studies. © The Author 2013.

The objective was to examine the role of tobacco smoking and alcohol drinking in the incidence of oral cavity cancer by subsite in France, a high-incidence area. We analysed detailed data on lifelong tobacco smoking and alcohol drinking from 772 oral cavity cancer cases and 3555 controls included in a population-based case-control study, the ICARE study. Tobacco smoking increased the risk of oral cavity cancer even for the smaller quantities and durations, whereas alcohol drinking increased this risk only in heavy drinkers who were also ever smokers. The combined effect of smoking and drinking was greater than multiplicative. The floor of the mouth was the subsite that was the most affected by the harmful effects of tobacco and alcohol, whereas the gums were less susceptible. The risk associated with tobacco and alcohol consumption did not differ between intraoral cavity and subsites usually included in the oropharynx (soft palate and base of the tongue). Population-attributable risks for oral cavity cancer were 78.6% for tobacco smoking, 7.3% for alcohol drinking and 80.7% for tobacco and/or alcohol consumption. These results indicate that regular oral check-ups should be targeted at smokers and heavy drinkers, and that prevention efforts should be focused on smoking cessation.

To assess the risk of lung cancer associated with occupations and industries.A French population-based case-control study included 2923 cases and 3555 controls. Lifelong occupational history was collected. Two lists of occupations known (A) or suspected (B) to be associated with lung cancer were used. Occupations and industries not included in these lists were also explored.Among men, the smoking-adjusted odds ratio was 1.97 for list A (attributable fraction: 12.3%), 1.4 for list B (due especially to carpenters/joiners and transport workers). Among unlisted occupations, excess risks were found for welders, plumbers, and several construction crafts. Odds ratios among women were elevated for list A, list B (due especially to launderers/dry cleaners), cleaners and hairdressers.These results confirm the role of known occupations and give insight into new occupational risk factors among men and women.

The association between body mass index (BMI) and lung cancer is still disputed because of possible residual confounding by smoking and preclinical weight loss in case–control studies. We examined this association using data from the multicenter ICARE study in France, a large, population-based case–control study. A total of 2,625 incident lung cancer cases and 3,381 controls were included. Weight was collected at interview, 2 years before the interview, and at age 30. Lifetime smoking exposure was calculated using the comprehensive smoking index (CSI). Adjusted odds ratios (aORs) and 95 % confidence intervals were estimated by unconditional logistic regression and controlled for age, area, education, CSI, occupational exposure, previous chronic bronchitis, and parental history of lung cancer. We also examined the role of weight change. Analyses were stratified by smoking status and sex. When compared with that of men with normal BMI 2 years before the interview, lung cancer aORs (95 % CI) among men with BMIs of

Background The incidence of female lung cancer in developed countries has been increasing since 1950. In order to have recent and reliable data on the association between cigarette smoking and the risk of lung cancer in women, we analysed cases from a French population-based case–control study. Methods The ICARE study is a multicenter case–control study on respiratory cancers (lung and UADT cancers), set up in 10 departements that include a general cancer registry. We included 648 women lung cancer cases up to 76 years of age, with a histologically confirmed primary lung cancer. The 775 controls were randomly selected from the general population and frequency-matched with cases by age and departement . Results Overall, smoking cigarettes at some time was associated with a 8-fold increase in lung cancer risk (OR = 8.2, 95% CI 6.0–11.4). A dose–response relationship was observed as a function of duration, intensity and pack-years. Using restricted splines cubic models, we have shown that intensity dose-response departed significantly from linearity while the risk increased linearly with duration and decreased linearly with time since cessation. The following characteristics were associated with a higher relative risk: smoke inhalation, smoking non-filter cigarettes, smoking dark tobacco cigarettes and starting at a young age. In addition, duration, intensity and time since cessation was significantly related with histological type. This was not the case for characteristics such as the use of a filter or not, the inhalation pattern, or the type of tobacco smoked. The proportion of lung cancer cases attributable to cigarette smoking was 55% (95% CI: [47–63%]). Conclusions Our results confirm that cigarette smoking is by far the most important cause of the current epidemic of lung cancer among French women and that the most important smoking-related variables for varying the risk of lung cancer are the duration, the intensity and the time since cessation.

Objectives To investigate the association between head and neck cancer (HNC) and occupation in men. Methods As part of a large population based case-control study conducted in France between 2002 and 2007 (the ICARE study), 1924 incident male HNC cases and 2780 male population controls were interviewed. Detailed lifetime occupational histories, as well as information on potential confounders were collected. A preliminary analysis based on job titles was performed. Odds-ratios (OR), adjusted for age, smoking and alcohol drinking, and 95% CIs were estimated using unconditional logistic regression. Results The risk of HNC was significantly increased for dry cleaners (OR: 6.9, 95% CI 1.5-30.9), building caretakers and cleaners (OR: 2.0, 95% CI: 1.2 to 3.2), rubber and plastics product makers (OR: 1.9, 95% CI: 1.1-3.4), metal processors (OR: 1.9, 95% CI: 1.2 to 3.0), bricklayers and other construction workers (OR:1.7 ; 95% CI :1.4 to 2.1), plumbers and welders (OR: 1.5, 95% CI: 1.2 to 2.0), food and beverages processors (OR:1.5, 95% CI:1.1-2.0), cooks and waiters (OR: 1.5, 95% CI: 1.1 to .2.1), painters (OR: 1.4, 95% CI: 1.0 to 2.1), material-handling and related equipment operators, dockers and freight handlers (OR: 1.3, 95% CI : 1.0 to 1.6), blacksmiths, toolmakers and machine-tool operators (OR: 1.3, 95% CI: 1.0 to 1.6). Teachers, managers and clerical workers had a significantly decreased risk. Conclusions These preliminary results suggest that occupational factors may play a substantial role in the risk of HNC. Assessment of exposure to several substances is in progress, and will help identify specific causal agents.