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Purpose: To study the association between occupational exposure to metals including chromium, cadmium, nickel, and arsenic compounds, within a population-based study design, while adjusting for confounding factors. Methods: A population-based lung cancer case-control study in Central/Eastern Europe and UK was conducted in 1998-2003, including 2,853 cases and 3,104 controls. Exposure to 70 occupational agents was assessed by local expert-teams for all subjects. Odds ratios (OR) for exposure to dust and fumes/mist of chromium, nickel, cadmium, arsenic, as well as inorganic pigment dust and inorganic acid mist, were adjusting for smoking, age, center, sex, and exposure to other occupational agents including the metals under study. Results: Exposure to arsenic (prevalence = 1.4%) was associated with an increased lung cancer risk ((OR) 1.65, 95% confidence interval (95% CI):1.05-2.58). For chromium dust (prevalence = 4.8%, OR: 1.25, 95% CI: 0.95-1.65), a linear upward trend for duration and cumulative exposure was observed. A weak association was observed for exposure to cadmium fumes (prevalence = 1.8%, OR: 1.19, 95% CI: 0.77-1.82), which was strongest for the highest category of cumulative exposure (OR: 2.04, 95% CI: 1.07-3.90). No increased risk was observed for inorganic acid mist, inorganic pigment dust, or nickel, after adjustment for other metals. An independent effect of nickel cannot be excluded, due to its collinearity with chromium exposure. Conclusions: Occupational exposure to metals is an important risk factor for lung cancer. Although the strongest risk was observed for arsenic, exposure to chromium dust was most important in terms of attributable risk due to its high prevalence. © 2011 Springer Science+Business Media B.V.

Objective: To estimate the lung cancer risk attributable to occupational lung carcinogens. METHODS: Information was collected through interviews from 2624 newly diagnosed lung cancer cases and 2690 frequency-matched controls in Central and Eastern Europe. Industrial hygiene experts evaluated exposure to 70 occupational agents. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression and attributable fractions (AF) by Miettinens formula. RESULTS: Exposure to at least one occupational lung carcinogen resulted in an AF of 7.9% in men and 1.4% in women. Metals and silica contributed the most to the AF. The AF was highest for squamous cell carcinoma among men (11.4%) and for small cell carcinoma among women (7.1%); the effect of occupational lung carcinogens was stronger overall among current smokers. CONCLUSION: This estimation of the AF of occupational lung carcinogens is comparable to that estimated in other European studies, and cannot alone explain the high lung cancer rates in Central and Eastern Europe. Copyright © 2011 by American College of Occupational and Environmental Medicine.

Rationale: Diesel motor exhaust is classified by the International Agency for Research on Cancer as probably carcinogenic to humans. The epidemiologic evidence is evaluated as limited because most studies lack adequate control for potential confounders and only a few studies have reported on exposure-response relationships. Objectives: Investigate lung cancer risk associated with occupational exposure to diesel motor exhaust, while controlling for potential confounders. Methods: The SYNERGY project pooled information on lifetime work histories and tobacco smoking from13,304 cases and 16,282 controls from 11 case-control studies conducted in Europe and Canada. A general population job exposure matrix based on ISCO-68 occupational codes, assigning no, low, or high exposure to diesel motor exhaust, was applied to determine level of exposure. Measurements and Main Results: Odds ratios of lung cancer and 95% confidence intervals were estimated by unconditional logistic regression, adjusted for age, sex, study, ever-employment in an occupation with established lung cancer risk, cigarette pack-years, and time-since-quitting smoking. Cumulative diesel exposure was associated with an increased lung cancer risk highest quartile versus unexposed (odds ratio 1.31; 95%confidence interval, 1.19-1.43), and a significant exposure-response relationship (P value < 0.01). Corresponding effect estimates were similar in workers never employed in occupations with established lung cancer risk, and in women and neversmokers, although not statistically significant. Conclusions: Our results show a consistent association between occupational exposure to diesel motor exhaust and increased risk of lung cancer. This association is unlikely explained by bias or confounding, which we addressed by adjusted models ands ubgroup analyses. Copyright © 2011 American Thoracic Society.

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility., Author Summary We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.

The relationship between two measures of excess body weight, body mass index (BMI) and body size score, and risk of pancreatic cancer was examined among 574 pancreatic cancer cases and 596 frequency-matched controls from the Czech Republic and Slovakia enrolled between 2004 and 2009. Analyses using multivariable logistic regression showed an increased risk of pancreatic cancer associated with elevated quartiles of BMI at ages 20 [fourth quartile: odds ratio (OR) = 1.79, 95% confidence interval (CI): 1.23, 2.61] and 40 (fourth quartile: OR = 1.57, 95% CI: 1.09, 2.27) compared to the lowest quartile. Consistent results were observed for body size score at ages 20 (high versus low: OR = 1.66, 95% CI: 1.08, 2.57) and 40 (medium versus low: OR = 1.36, 95% CI: 1.00, 1.86), but no association was found for BMI and body size score at 2 years before the interview. Stronger risk estimates for BMI were observed in males than females, particularly at age 20, but the analysis of body size yielded similar estimates by sex. When considering excess body weight at both ages 20 and 40 jointly, the highest risk estimates were observed among subjects with elevated levels at both time periods in the analysis of BMI (OR = 1.86, 95% CI: 1.32, 2.62) and body size (OR = 1.53, 95% CI: 1.09, 2.13). These findings, based on two different measures, provide strong support for an increased risk of pancreatic cancer associated with excess body weight, possibly strongest during early adulthood.

Odds ratios for head and neck cancer increase with greater cigarette and alcohol use and lower body mass index (BMI; weight (kg)/height2 (m2)). Using data from the International Head and Neck Cancer Epidemiology Consortium, the authors conducted a formal analysis of BMI as a modifier of smoking- and alcohol-related effects. Analysis of never and current smokers included 6,333 cases, while analysis of never drinkers and consumers of ≤10 drinks/day included 8,452 cases. There were 8,000 or more controls, depending on the analysis. Odds ratios for all sites increased with lower BMI, greater smoking, and greater drinking. In polytomous regression, odds ratios for BMI (P = 0.65), smoking (P = 0.52), and drinking (P = 0.73) were homogeneous for oral cavity and pharyngeal cancers. Odds ratios for BMI and drinking were greater for oral cavity/pharyngeal cancer (P < 0.01), while smoking odds ratios were greater for laryngeal cancer (P < 0.01). Lower BMI enhanced smoking- and drinking-related odds ratios for oral cavity/pharyngeal cancer (P < 0.01), while BMI did not modify smoking and drinking odds ratios for laryngeal cancer. The increased odds ratios for all sites with low BMI may suggest related carcinogenic mechanisms; however, BMI modification of smoking and drinking odds ratios for cancer of the oral cavity/pharynx but not larynx cancer suggests additional factors specific to oral cavity/pharynx cancer.

Background: Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens. Methods: We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies. Results: Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P20 CPD) [odds ratio (OR)=1.13, 95% confidence interval (CI) 0.96-1.34, P=0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P

Background: Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers. Methods: We pooled individual-level data from case-control studies in the International Head and Neck Cancer Epidemiology Consortium. Data were available from 13 studies on drinking cessation (9167 cases and 12 593 controls), and from 17 studies on smoking cessation (12 040 cases and 16 884 controls). We estimated the effect of quitting smoking and drinking on the risk of head and neck cancer and its subsites, by calculating odds ratios (ORs) using logistic regression models. Results: Quitting tobacco smoking for 1-4 years resulted in a head and neck cancer risk reduction [OR 0.70, confidence interval (CI) 0.61-0.81 compared with current smoking], with the risk reduction due to smoking cessation after =20 years (OR 0.23, CI 0.18-0.31), reaching the level of never smokers. For alcohol use, a beneficial effect on the risk of head and neck cancer was only observed after =20 years of quitting (OR 0.60, CI 0.40-0.89 compared with current drinking), reaching the level of never drinkers. Conclusions: Our results support that cessation of tobacco smoking and cessation of alcohol drinking protect against the development of head and neck cancer. © The Author 2009; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Although cigarette smoking and alcohol consumption increase risk for head and neck cancers, there have been few attempts to model risks quantitatively and to formally evaluate cancer site-specific risks. The authors pooled data from 15 case-control studies and modeled the excess odds ratio (EOR) to assess risk by total exposure (pack-years and drink-years) and its modification by exposure rate (cigarettes/day and drinks/day). The smoking analysis included 1,761 laryngeal, 2,453 pharyngeal, and 1,990 oral cavity cancers, and the alcohol analysis included 2,551 laryngeal, 3,693 pharyngeal, and 3,116 oval cavity cancers, with over 8,000 controls. Above 15 cigarettes/day, the EOR/pack-year decreased with increasing cigarettes/day, suggesting that greater cigarettes/day for a shorter duration was less deleterious than fewer cigarettes/day for a longer duration. Estimates of EOR/pack-year were homogeneous across sites, while the effects of cigarettes/day varied, indicating that the greater laryngeal cancer risk derived from differential cigarettes/day effects and not pack-years. EOR/drink-year estimates increased through 10 drinks/day, suggesting that greater drinks/day for a shorter duration was more deleterious than fewer drinks/day for a longer duration. Above 10 drinks/day, data were limited. EOR/drink-year estimates varied by site, while drinks/day effects were homogeneous, indicating that the greater pharyngeal/oral cavity cancer risk with alcohol consumption derived from the differential effects of drink-years and not drinks/day.

Background Obesity is a risk factor for several cancers although appears to have an inverse association with cancers strongly related to tobacco. Studying obesity is difficult due to numerous biases and confounding. Methods To avoid these biases we used a Mendelian randomization approach incorporating an analysis of variants in the FTO gene that are strongly associated with BMI levels among 7000 subjects from a study of lung, kidney and upper-aerodigestive cancer. Results The FTO A allele which is linked with increased BMI was associated with a decreased risk of lung cancer (allelic odds ratio (OR) = 0.92, 95% confidence interval (CI) 0.84–1.00). It was also associated with a weak increased risk of kidney cancer, which was more apparent before the age of 50 (OR = 1.44, CI 1.09–1.90). Conclusion Our results highlight the potential for genetic variation to act as an unconfounded marker of environmentally modifiable factors, and offer the potential to obtain estimates of the causal effect of obesity. However, far larger sample sizes than studied here will be required to undertake this with precision.

SUMMARY Background: Social inequalities have been shown to contribute to the risk of lung cancer in industrialized countries, but it is unclear whether they also play a role in former socialist countries of Europe. Methods: A case-control study involving 3,403 cases and 3,670 controls was conducted in Central European countries (Czech Republic, Hungary, Poland, Romania, Slovakia), Russia, and in the UK. Indicators of socioeconomic status, including education and white/blue collar occupation based on lifetime occupations were analysed as indicators of risk factors for lung cancer development, after adjustment for tobacco smoking and exposure to occupational carcinogens. Results: Both indicators of socioeconomic status: low education and blue collar occupations were found as significant risk factors for lung cancer in men. The odds ratio of lung cancer for blue collar occupations compared to white collar occupations was 1.37 (95% confidence interval 1.15–1.62), that for low education compared to high education (analysis restricted to Central European countries) was 1.35 (95% confidence interval 1.03–1.77). No such effects were observed in women. Conclusions: The confirmation of the significant inverse association between the indicators of socioeconomic status and lung cancer risk in men may serve as a strong incentive for adoption of occupational and public health measures in lung cancer prevention.

Alcohol and tobacco consumption are well-recognized risk factors for head and neck cancer (HNC). Evidence suggests that genetic predisposition may also play a role. Only a few epidemiologic studies, however, have considered the relation between HNC risk and family history of HNC and other cancers. We pooled individual-level data across 12 case-control studies including 8,967 HNC cases and 13,627 controls. We obtained pooled odds ratios (OR) using fixed and random effect models and adjusting for potential confounding factors. All statistical tests were two-sided. A family history of HNC in first-degree relatives increased the risk of HNC OR = 1.7, 95% confidence interval, CI, 1.2-2.3). The risk was higher when the affected relative was a sibling (OR = 2.2, 95% CI 1.6-3.1) rather than a parent (OR = 1.5, 95% CI 1.1-1.8) and for more distal HNC anatomic sites (hypopharynx and larynx). The risk was also higher, or limited to, in subjects exposed to tobacco. The OR rose to 7.2 (95% CI 5.5-9.5) among subjects with family history, who were alcohol and tobacco users. A weak but significant association (OR = 1.1, 95% CI 1.0-1.2) emerged for family history of other tobacco-related neoplasms, particularly with laryngeal cancer (OR = 1.3, 95% CI 1.1-1.5). No association was observed for family history of nontobacco-related neoplasms and the risk of HNC (OR = 1.0, 95% CI 0.9-1.1). Familial factors play a role in the etiology of HNC. In both subjects with and without family history of HNC, avoidance of tobacco and alcohol exposure may be the best way to avoid HNC. © 2008 Wiley-Liss, Inc.

An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were collected as control samples and were genotyped with more than 300 000 SNPs in genome-wide association studies using the Illumina Infinium platform. A major East-West gradient from Russian (Moscow) samples to Spanish samples was identified as the first principal component (PC) of the genetic diversity. The second PC identified a North-South gradient from Norway and Sweden to Romania and Spain. Variation of frequencies at markers in three separate genomic regions, surrounding LCT, HLA and HERC2, were strongly associated with this gradient. The next 18 PCs also accounted for a significant proportion of genetic diversity observed in the sample. We present a method to predict the ethnic origin of samples by comparing the sample genotypes with those from a reference set of samples of known origin. These predictions can be performed using just summary information on the known samples, and individual genotype data are not required. We discuss issues raised by these data and analyses for association studies including the matching of case-only cohorts to appropriate pre-collected control samples for genome-wide association studies.

Mechanistic evidence linking chromosomal aberration (CA) to early stages of cancer has been recently supported by the results of epidemiological studies that associated CA frequency in peripheral lymphocytes of healthy individuals to future cancer incidence. To overcome the limitations of single studies and to evaluate the strength of this association, a pooled analysis was carried out. The pooled database included 11 national cohorts and a total of 22 358 cancer-free individuals who underwent genetic screening with CA for biomonitoring purposes during 1965-2002 and were followed up for cancer incidence and/ or mortality for an average of 10.1 years; 368 cancer deaths and 675 incident cancer cases were observed. Subjects were classified within each laboratory according to tertiles of CA frequency. The relative risk (RR) of cancer was increased for subjects in the medium [RR = 1.31, 95% confidence interval (CI) = 1.07-1.60] and in the high (RR = 1.41; 95% CI = 1.16-1.72) tertiles when compared with the low tertile. This increase was mostly driven by chromosome-type aberrations. The presence of ring chromosomes increased the RR to 2.22 (95% CI = 1.34-3.68). The strongest association was found for stomach cancer [RRmedium = 1.17 (95% CI = 0.37-3.70), RRhigh = 3.13 (95% CI = 1.17-8.39)]. Exposure to carcinogens did not modify the effect of CA levels on overall cancer risk. These results reinforce the evidence of a link between CA frequency and cancer risk and provide novel information on the role of aberration subclass and cancer type. © The Author 2008. Published by Oxford University Press. All rights reserved.

Letter; International audience; Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually1. 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 × 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 × 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

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10-10 and 10 -9, respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology. © 2008 Nature Publishing Group.

Objective: The incidence of squamous cell carcinoma of upper aerodigestive tract (UADT: oral cavity, pharynx, larynx, and esophagus) has been increasing in central and eastern European countries. We investigated the relationship between diet and UADT cancers in these high risk areas. Methods: We used data from hospital-based case-control study of 948 UADT cancer cases and 1,228 controls conducted in Romania, Hungary, Poland, Russia, Slovakia, and Czech Republic. Standardized questionnaire were used to collect information on 23 different food items, along with alcohol and tobacco consumptions. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the UADT cancers after adjusting for center, age, sex, tobacco & alcohol intake, and other food groups. Results: Consumption of dairy product was negatively associated with selected UADT cancers: larynx (OR: 0.38, CI: 0.23-0.62) and esophagus (OR: 0.55, CI: 0.33-0.93). While consumption of yellow/orange vegetables were inversely associated with oral/pharyngeal and laryngeal cancer (OR: 0.53, CI: 0.35-0.81 and OR: 0.62, CI: 0.38-1.00, respectively), preserved vegetable was positively associated with oral/pharyngeal and laryngeal cancer risk (ptrend < 0.01 for both). Conclusion: Specific dietary components may play a role in the development of UADT cancers in the high-risk region of central and eastern Europe. © 2008 Springer Science+Business Media B.V.

Folate has been hypothesized to protect against aero-digestive cancers although the evidence is not yet conclusive due to possible confounding by other dietary factors. Sequence variants in folate pathway were suggested to be associated with plasma folate levels and are unlikely to be confounded by other lifestyle factors. We therefore investigated the effects of key folate genetic variants on the risk of aero-digestive cancers and their potential effect modification by folate intake in a multicenter study in Central Europe. A total of 2250 lung cases, 811 upper aero-digestive tract cases and 2899 controls were recruited with blood samples. The methylenetetrahydrofolate reductase (MTHFR) C677T variant was associated with an increased risk of lung cancer with an odds ratio (OR) for homozygote variant of 1.37 [95% confidence interval (CI) =1.10-;1.71]. The two MTHFR variants were in strong linkage disequilibrium, and 677T-1298A appeared to be the primary haplotype associated with cancer risk. The risk estimates for MTHFR 677T/677T genotype was more prominent among lung cancer patients with young onset (OR=1.92,95% CI =1.12-3.29). When stratified by dietary intake of folate, the effect of the MTHFR 677T variant was more prominent among subjects with low intake of folate: the ORs for 677T/677T genotype among subjects with the lowest decile were 2.60 (95% CI =1.39-4.88) and 4.14 (95% CI =1.47-11.7) for lung and upper aero-digestive tract cancer, respectively. In conclusion, we identified a moderate effect of MTHFR C677T on lung cancer risk and a possible effect modification by folate intake that is consistent with the functional data. These results support an important role of folate in protecting against tobacco-related cancers. © The Author 2007. Published by Oxford University Press. All rights reserved.

Cancers of the upper aerodigestive tract (UADT), comprising the oral cavity, pharynx, larynx and oesophagus, account for 5.2% of all cancers cases worldwide. The major risk factors, tobacco and alcohol can directly or indirectly generate DNA damage, which if unrepaired can give rise to mutations, unregulated cell growth and apoptosis induction. To clarify the role of DNA repair and cell cycle control proteins in UADT cancer susceptibility, we studied the risk in relation to 28 SNPs in 18 DNA repair enzymes and 9 SNPs in 7 cell cycle control genes. A case-control study was conducted from 2000 to 2002 in six centers from Romania, Poland, Russia, Slovakia and the Czech Republic. Patients diagnosed with squamous cell carcinoma of the UADT (n = 811) and controls with a recent diagnosis of diseases unrelated to tobacco and alcohol (n = 1083) were recruited. For UADT cancer risk, associations were observed for the homozygous carriers of the variant alleles of MGMT L84F [odds ratio (OR) 2.35, 95% confidence interval (CI) 1.32-4.20], MGMT 171C > T (OR 2.24, 95% CI 1.20-4.17) and OGG1 S326C (OR 2.07, 95% CI 1.15-3.73) whilst three variants were associated with a protective effect (XPA 23G > A, P for trend 0.022, APEX Q51H, P for trend 0.036, CHEK2 intron 9-200T > C, P for trend 0.009). Several other sequence variants showed associations with specific cancers without an overall association with UADT cancer. While some of these associations are consistent with previous studies, we cannot rule out the possibility of false-positive associations. The positive findings should be explored in another large-scale study on UADT cancers. © 2007 Oxford University Press.

Incidence rates for laryngeal cancer in Central Europe are among the highest in the world. The authors recruited cases and controls between 2000 and 2002 for the Central and Eastern Europe Multicenter Study to investigate the role of tobacco and alcohol as causes of laryngeal cancer in this region. A total of 384 incident squamous cell cases were included, comprising 254 glottic and 108 supraglottic cancers. Hospital controls were chosen from within the same catchment area, from diseases unrelated to tobacco or alcohol (n = 918). Significant dose-response trends for frequency and duration of tobacco use were observed for both supraglottic and glottic cancers, with potentially a more important effect for supraglottic cancer. Quitting smoking was protective against laryngeal cancers after 5 years. Any increases in risk for alcohol drinking were generally moderate and nonsignificant. A greater than multiplicative interaction was observed between tobacco and alcohol on the risk of laryngeal cancer (p = 0.04). Approximately 87% of laryngeal cancer cases in Central Europe are attributable to tobacco use, of which 75% and 12% are due to current and past smoking, respectively. Approximately 39% are attributable to the interaction between alcohol and tobacco. Preventive efforts to encourage current smokers to quit are likely to be the most effective way to reduce the incidence of laryngeal cancer in this region. Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved.

Objectives: To investigate the contribution of occupational exposure to asbestos and man-made vitreous fibres (MMVF) to lung cancer in high-risk populations in Europe. Methods: A multicentre case-control study was conducted in six Central and Eastern European countries and the UK, during the period 1998–2002. Comprehensive occupational and sociodemographic information was collected from 2205 newly diagnosed male lung cancer cases and 2305 frequency matched controls. Odds ratios (OR) of lung cancer were calculated after adjusting for other relevant occupational exposures and tobacco smoking. Results: The OR for asbestos exposure was 0.92 (95% CI 0.73 to 1.15) in Central and Eastern Europe and 1.85 (95% CI 1.07 to 3.21) in the UK. Similar ORs were found for exposure to amphibole asbestos. The OR for MMVF exposure was 1.23 (95% CI 0.88 to 1.71) with no evidence of heterogeneity by country. No synergistic effect either between asbestos and MMVF or between any of them and smoking was found. Conclusion: In this large community-based study occupational exposure to asbestos and MMVF does not appear to contribute to the lung cancer burden in men in Central and Eastern Europe. In contrast, in the UK the authors found an increased risk of lung cancer following exposure to asbestos. Differences in fibre type and circumstances of exposure may explain these results.

Objective: We sought to evaluate the role of occupation and industry in lung carcinogenesis in six countries in Central and Eastern Europe. Methods: This multi-center case-control study included 2,056 male and 576 female lung cancer incidence cases diagnosed from 1998 to 2001 and 2,144 male and 727 female controls frequency-matched for sex and age. Unconditional regression models were applied to calculate the odds ratios after controlling for potential confounders including age (5-year groups), study center (15 centers), and tobacco pack-years. Results: Elevated odds ratios (ORs) were found for men employed as production workers (OR 1.45, 95% CI 1.22-1.72), bookkeepers and cashiers (1.81, 1.03-3.24), general farmers (1.67, 1.08-2.60), livestock workers (2.54, 1.09-5.88), miners (2.17, 1.47-3.23), toolmakers and metal patternmakers (2.56, 1.34-4.94), glass formers (2.55, 1.18-5.50), dockworkers, and freight handlers (1.49, 1.04-2.12). Industries with elevated risk among men included mining (1.75, 1.20-2.57), manufacture of cement, lime, or plaster (3.62, 1.11-12.00), casting of metals (2.00, 1.17-3.45), manufacture of electric motors (2.18, 1.24-3.86). For women, elevated ORs were found for medical, dental, veterinary doctors (2.54, 1.01-6.31), librarians and curators (7.03, 1.80-27.80), sewers 3.63 (1.12-10.23). Conclusions: This study identifies new areas for further, explanatory analyses, especially in production work, and indicates new possible sources of exposure to cancer risk for women. © 2007 Springer Science + Business Media B.V.

CHEK2 is a key cell cycle control gene encoding a pluripotent kinase that can cause arrest or apoptosis in response to unrepaired DNA damage. We report a large case-control study of a non-functional variant that had previously been expected to increase cancer rates. Four thousand and fifteen cancer patients (2250 lung, 811 squamous upper aero-digestive and 954 kidney) and 3052 controls in central Europe were genotyped for the mis-sense variant rs17879961 (replacement of T by C), which changes an amino acid (I157T) in an active site of the gene product. The heterozygous (T/C) genotype was associated with a highly significantly lower incidence of lung cancer than the common T/T genotype [relative risk (RR), T/C versus T/T, 0.44, with 95% confidence interval (CI) 0.31-0.63, P < 0.00001] and with a significantly lower incidence of upper aero-digestive cancer (RR 0.44, CI 0.26-0.73, (P = 0.001; P = 0.000001 for lung or upper aero-digestive cancer). Protection was significantly greater for squamous than adenomatous lung cancer (P = 0.001). There was an increase of borderline significance in kidney cancer (RR 1.44, CI 0.99-2.00, P = 0.06). This unexpected halving of tobacco-related cancer (since replicated independently) implies much greater absolute risk reduction in smokers than in non-smokers. The mechanism is unknown: perhaps squamous stem cell apoptosis following smoke exposure causes net harm (e.g. by forcing nearby stem cells to divide before they have repaired their own DNA damage from tobacco smoke). If so, reducing the rate of apoptosis by reducing CHEK2 activity could be protective - although not smoking would be far more so. © The Author 2007. Published by Oxford University Press. All rights reserved.

Background: At least 75% of head and neck cancers are attributable to a combination of cigarette smoking and alcohol drinking. A precise understanding of the independent association of each of these factors in the absence of the other with the risk of head and neck cancer is needed to elucidate mechanisms of head and neck carcinogenesis and to assess the efficacy of interventions aimed at controlling either risk factor. Methods: We examined the extent to which head and neck cancer is associated with cigarette smoking among never drinkers and with alcohol drinking among never users of tobacco. We pooled individual-level data from 15 case - control studies that included 10 244 head and neck cancer case subjects and 15 227 control subjects, of whom 1072 case subjects and 5775 control subjects were never users of tobacco and 1598 case subjects and 4051 control subjects were never drinkers of alcohol. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. All statistical tests were two-sided. Results: Among never drinkers, cigarette smoking was associated with an increased risk of head and neck cancer (OR for ever versus never smoking = 2.13, 95% CI = 1.52 to 2.98), and there were clear dose - response relationships for the frequency, duration, and number of pack-years of cigarette smoking. Approximately 24% (95% CI = 16% to 31%) of head and neck cancer cases among nondrinkers in this study would have been prevented if these individuals had not smoked cigarettes. Among never users of tobacco, alcohol consumption was associated with an increased risk of head and neck cancer only when alcohol was consumed at high frequency (OR for three or more drinks per day versus never drinking = 2.04, 95% CI = 1.29 to 3.21). The association with high-frequency alcohol intake was limited to cancers of the oropharynx/hypopharynx and larynx. Conclusions: Our results represent the most precise estimates available of the independent association of each of the two main risk factors of head and neck cancer, and they exemplify the strengths of large-scale consortia in cancer epidemiology. © The Author 2007. Published by Oxford University Press.

Delahaye-Sourdeix, Manon Oliver, Javier Timofeeva, Maria N Gaborieau, Valerie Johansson, Mattias Chabrier, Amelie Wozniak, Magdalena B Brenner, Darren R Vallee, Maxime P Anantharaman, Devasena Lagiou, Pagona Holcatova, Ivana Richiardi, Lorenzo Kjaerheim, Kristina Agudo, Antonio Castellsague, Xavier Macfarlane, Tatiana V Barzan, Luigi Canova, Cristina Thakker, Nalin S Conway, David I Znaor, Ariana Healy, Claire M Ahrens, Wolfgang Zaridze, David Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Fabianova, Eleonora Mates, Ioan Nicolae Bencko, Vladimir Foretova, Lenka Janout, Vladimir Curado, Maria Paula Koifman, Sergio Menezes, Ana Wunsch-Filho, Victor Eluf-Neto, Jose Boffetta, Paolo Garrote, Leticia Fernandez Serraino, Diego Lener, Marcin Jaworowska, Ewa Lubinski, Jan Boccia, Stefania Rajkumar, Thangarajan Samant, Tanuja A Mahimkar, Manoj B Matsuo, Keitaro Franceschi, Silvia Byrnes, Graham Brennan, Paul McKay, James D eng 1R03DE020116/DE/NIDCR NIH HHS/ R01 CA092039 05/05S1/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural 2015/03/21 06:00 PLoS One. 2015 Mar 20;10(3):e0117639. doi: 10.1371/journal.pone.0117639. eCollection 2015.; International audience; Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

The authors have calculated cumulative risks of lung cancer from a case-control study conducted between 1998 and 2002 involving 2,633 lung cancer cases and 2,884 controls in Hungary, Poland, the Czech Republic, Slovakia, Romania, and Russia. The odds ratios for smoking history were combined with national lung cancer mortality rates to obtain the cumulative risk of lung cancer. The cumulative risk of death from lung cancer by the age of 75 years among current male smokers was 14.6% in Romania and Russia and 15.8% in Poland, similar to levels reported in Western Europe, although higher risks were found in the Czech Republic (19.8%), Hungary (21.9%), and Slovakia (28.2%). Cumulative risks of lung cancer death among never smokers of over 1% were observed in Hungary among both men and women and among men in Poland. The effect of quitting smoking on the lifetime cumulative risk was substantial, with between 67% and 83% of lung cancer risk among men being avoided by quitting before the age of 50 years. This substantial reduction in risk among former smokers confirms that lung cancer mortality in Central Europe over the next three decades will be determined by the extent to which current smokers can successfully quit smoking. Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved.

Objectives: The purpose of this study was to investigate the role of polymorphisms of genes involved in inflammation in the risk of cancers of the upper aerodigestive tract (UADT). Methods: We have evaluated the role of polymorphisms in key genes related to inflammation, namely IL1B (rs1143627), COX2/PTGS2 (rs5275), and IL8 (rs4073) in a large case-control study comprising 811 UADT cancer cases and 1,083 controls. Results: An association was observed for squamous cell carcinoma of the pharynx for a polymorphism in the promoter of the IL1B gene, with an OR of 2.39 (95% CI = 1.19-4.81) for the homozygotes for the minor allele A promoter polymorphism of IL8 was associated with decreased risk of laryngeal cancer, with an OR of 0.70 (95% CI = 0.50-0.98) for carriers of the minor allele. Conclusions: To our knowledge, this is the first report on the role of these polymorphisms with respect to UADT carcinogenesis. Our results suggest that inflammation-related polymorphisms play a role, albeit minor, in the risk of developing cancers of the upper aerodigestive tract. © 2007 Springer Science+Business Media B.V.

Inequalities in health between socio-economic groups are a major public health concern. The current authors studied associations between parental socio-economic status (SES) and children's respiratory and allergic symptoms in 13 diverse countries, including the Russian Federation, North America (Canada and the USA), and countries across Eastern and Western Europe. Data of 57,000 children aged 6-12 yrs, originating from eight cross-sectional studies, were analysed. SES was defined by parental education. Respiratory and allergic symptoms were defined by parental questionnaire reports. Multiple logistic regressions showed that low parental education was associated with a decreased risk of inhalant allergy and itchy rash in school children. Furthermore, low parental education was associated with an increased prevalence of wheeze and nocturnal dry cough. No clear association was found between parental education and prevalence of doctor-diagnosed asthma and bronchitis. Part of the difference between socio-economic groups with regard to their children's symptoms was explained by established risk factors, such as parental allergy, smoking during pregnancy, pet ownership, crowding, mould/moisture in the home, use of gas for cooking, and air pollution (particulate matter with a diameter of

The Arsenic Health Risk Assessment and Molecular Epidemiology (ASHRAM) project is an international study funded by the European Commission and managed by an international consortium. For this project, areas in Slovakia, Romania and Hungary were selected for evaluation. The objectives of the study included: (1) to quantify the cancer risks in relation to arsenic ingestion via drinking water; (2) to assess the effect of inter-individual variation in arsenic metabolism and DNA repair on carcinogenic risk; and (3) to review current risk assessment models for arsenic and cancer, and to evaluate the impact of these models with regards to the adequacy of the current and proposed drinking water standards. The recruitment and interviewing of study participants, sample collection, and data from an arsenic exposure model are presented.

The subject of this analysis was a database of 1,503 non-melanoma skin cancer cases (756 in men and 747 in women) collected from 1977 to 1996 in a region in central Slovakia contaminated by emissions from a power plant that burned coal with a high arsenic content (ranging between 900 to 1,500 g per metric ton of dry coal). Exposure assessment of the non-occupationally exposed population was accomplished by analyzing hair and urine samples from groups of 10 year old boys living at different locations up to 30 km from the power plant. Basic epidemiological data of the cancer cases were obtained in a questionnaire about personal information and family, residential and occupational history. Our study base represented 1,335 thousands men/year and 1,337 thousands women/year for the 20 year study of a population of approximate size of 125,000 inhabitants. The age-standardized incidence of non-melanoma skin cancer (each confirmed by histological examination) ranged from 43.7 to 92.0 in men and from 34.6 to 79.1 in women calculated for four 5-year periods during the study). Analysis of our database demonstrates a positive correlation between human cumulative arsenic exposure and nonmelanoma skin cancer incidence.

BACKGROUND: Tobacco smoking is the main cause for lung cancer worldwide, making it difficult to examine the carcinogenic role of other risk factors because of possible confounding by smoking. Therefore, the present study aimed to investigate the association between lung cancer and occupation independent of smoking. METHODS: A case-control study of lung cancer was carried out between March 1998 and January 2002 in 16 centers from 7 European countries, including 223 never-smoking cases and 1039 controls. Information on lifestyle and occupation was obtained through detailed questionnaires. Job and industries were classified as entailing exposure to known or suspected carcinogens; in addition, expert assessment provided exposure estimates to specific agents. RESULTS: The odds ratio of lung cancer among women employed for more than 12 years in suspected high-risk occupations was 1.75 (95% confidence interval = 0.63-4.85). A comparable increase in risk was not detected for employment in established high-risk occupations or among men. Increased risk of lung cancer was suggested among individuals exposed to nonferrous metal dust and fumes, crystalline silica, and organic solvents. CONCLUSION: Occupations were found to play a limited role in lung cancer risk among never-smokers. Jobs entailing exposure to suspected lung carcinogens should receive priority in future studies among women. Nonferrous metal dust and fumes and silica may exert a carcinogenic effect independently from smoking. © 2006 Lippincott Williams & Wilkins, Inc.

A multicenter case-control study was conducted during 1999-2002 in four European countries (Poland, Romania, Russia, and Slovakia) to evaluate the role of occupational exposures in risk of laryngeal/hypopharyngeal cancer. Male cancer cases (34 hypopharyngeal, 316 laryngeal) with full data on occupational history and nonoccupational factors were compared with 728 hospital controls for occupational exposure to 73 suspected carcinogens. Occupational history was evaluated by industrial hygienists blinded to case/control status. Elevated risks for ever exposure to coal dust were found for both hypopharyngeal (odds ratio (OR) = 4.19, 95% confidence interval (CI): 1.18, 14.89) and laryngeal (OR = 1.81, 95% CI: 0.94, 3.47) cancer, with clear dose-response patterns. Inclusion of a 20-year lag in the analysis strengthened these associations. Hypopharyngeal cancer risk was also significantly associated with exposure to mild steel dust (OR = 3.04, 95% CI: 1.39, 6.64) and iron compounds and fumes (OR = 2.74, 95% CI: 1.29, 5.84), without clear dose-response relations. Laryngeal cancer was significantly associated with exposure to hard-alloys dust (OR = 2.23, 95% CI: 1.08, 4.57) and chlorinated solvents (OR = 2.18, 95% CI: 1.03, 4.61), without dose-response relations. A possible link between high formaldehyde exposure and laryngeal cancer was suggested. No association was found for exposure to asbestos or inorganic acid mists. These data indicate that occupational exposure to coal dust may play a role in laryngeal and hypopharyngeal cancer. Other possible relations need further evaluation. Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved.

CHEK2 is a cell cycle control gene encoding for checkpoint kinase 2, which acts as a tumor suppressor by causing arrest or apoptosis in response to unrepaired DNA damage. Inherited mutations in the CHEK2 gene have been reported to increase the risk of several cancers, although a paradoxical decrease in risk of tobacco-related lung and head and neck cancers was reported. An association between CHEK2 mutations and pancreatic cancer risk has not been reported. Missense variant rs17879961 (replacement of T by C, resulting in the change of Isoleucine by Threonine at position 157 of the protein [I157T]) has been shown to be very rare in the US and western Europe populations ( Citation Format: Ghislaine Scelo, James McKay, Ivana Holcatova, Vladimir Janout, Lenka Foretova, Eleonora Fabianova, Amelie Chabrier, Valerie Gaborieau, Paul Brennan. Uncommon CHEK2 missense variant and reduced risk of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2213. doi:10.1158/1538-7445.AM2014-2213

Inflammation is a contributing factor in pathogenesis of many cancers ([1][1]). Cigarette smoke increases expression of inflammatory mediators in airway epithelial cells as well as immune cells ([2][2]). Chronic inflammation, arising as a result of continuous exposure to tobacco components, may

Exposure to fuel from cooking and heating has not been studied in Europe, where lung cancer rates are high and many residents have had a long tradition of burning coal and unprocessed biomass. Study subjects included 2,861 cases and 3,118 controls recruited during 1998-2002 in the Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, and the United Kingdom. The odds ratio of lung cancer associated with solid fuel use was 1.22 (95% confidence interval (CI): 1.04, 1.44) for cooking or heating, 1.37 (95% CI: 0.90, 2.09) for solid fuel only for cooking, and 1.24 (95% CI: 1.05, 1.47) for solid fuels used for both cooking and heating. Risk increased relative to the percentage of time that solid fuel was used for cooking (p(trend)0.0001), while no risk increase was detected for solid fuel used for heating. The odds ratio of lung cancer in whole-life users of solid cooking fuel was 1.80 (95% CI: 1.35, 2.40). Switching to nonsolid fuels resulted in a decrease in risk. The odds ratio for the longest duration of time since switching was 0.76 (95% CI: 0.63, 0.92). The data suggest a modest increased risk of lung cancer related to solid-fuel use for cooking rather than heating.

Polymorphisms of key genes of inflammation pathways may be involved in lung carcinogenesis. Cigarette smoke stimulates airway epithelial cells to release proinflammatory cytokines, such as interleukin-1β (IL-1β). IL-1β triggers a cascade of inflammation reaction through the induction of

Objectives Most cohort studies show an increased risk of lung cancer among hairdressers. We investigated the risk of lung cancer among hairdressers and barbers in a large pooled dataset, while controlling for smoking. Methods The SYNERGY project has pooled information on lifetime work histories (ISCO-68) and tobacco smoking from 16258 lung cancer cases and 19922 controls, including 20% women, from 12 case-control studies in European and Canada. ORs for lung cancer and 95% CIs were estimated by unconditional logistic regression, adjusted for age, sex, study, cigarette pack-years and time since quitting smoking. Results Less than 1% of the study population had ever worked as hairdresser or barber (145 cases, 140 controls). Hairdressers and barbers experienced a slight increase in lung cancer risk (OR 1.23; 95% CI 0.97 to 1.56), which disappeared after adjusting for smoking (OR 0.95; 95% CI 0.72 to 1.25). Results by duration of employment showed highest risks in hairdressers with short employment. Results were similar by gender and histology of lung cancer. We observed a slight and non-significant increase in risk for male barbers, particularly in barbers with the longest employment and after adjustment for smoking (OR 1.62; 95% CI 0.81 to 3.24). Conclusions We did not detect an increased risk of lung cancer overall among those who ever worked as hairdresser or barber. However, among male barbers we observed that risk increased with duration of employment, although not statistically significant.

Objectives SYNERGY9s primary scope is the investigation of joint effects of occupational lung carcinogens. Smoking will be explored as potential confounder and effect modifier. Methods The SYNERGY database has been developed as platform for pooling studies with detailed occupational and smoking information. Occupations and industries were coded according to international classifications. Smoking-status definitions were harmonised. We present lung cancer risk estimates for smoking for 13 169 cases and 16 010 controls. Results The database comprises 16 830 cases (13 397 men, 3 433 women) and 20 975 controls (16 309 men, 4666 women) from 13 studies (54 centres, 13 countries, recruitment 1985–2007). Among cases, 2% of men and 24% of women were never smokers. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and women but squamous cell carcinoma (SqCC) in male smokers. Current smoking was associated with an OR of 23.6 (95% CI 20.4 to 27.2) in men and 7.8 (95% CI 6.8 to 9.0) in women. ORs increased by intensity or duration of cigarette smoking more pronounced for SqCC and small cell lung cancer (SCLC) than for AdCa. Smoking cessation reduced the risks already shortly after quitting but risk in heavy smokers did not fully return to the baseline risk of never smokers. Conclusions The SYNERGY project is the largest collection of cases and controls with detailed occupational and smoking information. This database allows precise risk estimates for pulmonary carcinogens and in-depth analyses, for example, in never smokers or for the subtypes of lung cancer. Smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa.

Publisher Summary The relationship between respiratory tract deposition of airborne arsenic (As) and urinary excretion of total As was investigated in five workers during and following a 9-day maintenance activity involving exposure to high concentrations of As in fly ash. Full-shift air samples were collected in the breathing zone of each worker during each day of exposure. The resulting data on As mass versus particle size were analyzed using the U.S. environmental protection agency particle deposition model to estimate the deposited dose of As associated with the exposures. The total deposited dose of As over the exposure period was then compared with the total excretion of As in 24 hr urine samples collected during, and for two days following, the exposures to estimate the bioavailability of As in fly ash. The observed particle distributions consisted primarily of large, nonrespirable particles, greater than 6 μm in aerodynamic diameter, which would be expected to deposit in the nasopharynx or tracheobronchial region rather than in the deep lung. The average deposition efficiency was on the order of 75%, and the calculated bioavailabilities (fraction of deposited As excreted in urine) for each subject ranged from 1% to 25%, with an average value of 11%. These results support the conclusions of a previous study performed at the same location, which found that the relative urinary excretion of As from fly ash was much lower than had been reported for other exposures to airborne As, such as at copper smelters.

Objectives Exploratory analyses by occupation or industry are commonly conducted in case-control studies. However, cancer risks limited to certain jobs within an industry, or to a job within a given industry, become undetectable in the overall industry or job odds-ratio. Using the SYNERGY dataset we conducted an analysis based on occupations and industries combined. Methods Data included 10 917 male cases and 13 154 male controls. Industries and jobs were coded according to ISIC Revision 2 and ISCO 1968, respectively. Odds-ratios were computed for ISCO-ISIC combinations with ≥10 study subjects, adjusting for study, age, and smoking. To allow for multiple comparisons we applied a semi-Bayes approach, shrinking towards a group mean the estimate for each ISCO-ISIC combination, previously classified as: occupation known or suspected to entail lung cancer risk, other manual workers, other non-manual workers. Results Out of 1187 evaluated ISCO-ISIC combinations, 50 had an increased odds-ratio (p Conclusions The use of ISCO-SIC combinations and a semi-Bayes approach identified specific jobs within specific industries with an increased lung cancer risk.

Objectives We estimated the lung cancer risk following occupational exposure to carbon black while adjusting for smoking, and explored the effect of time-windows of carbon black exposure since recent studies have hypothesised that recent exposure is the most important time-window for carbon black exposure. Methods The multicenter case-control study on lung cancer was conducted from 1998 to 2002 in seven European countries; 2861 cases and 2936 controls were recruited. Occupational and socio-demographic information was collected through interviews. Industrial hygiene experts in each country evaluated exposure to 70 occupational agents, including carbon black. Unconditional logistic regression models were applied to calculate ORs and 95% CIs adjusting for centre, sex, other occupational exposures and tobacco smoking. Results The OR for ever exposure to carbon black was 1.64 (95% CI 1.09 to 2.46). We observed a significant dose-response trend for maximum intensity (p-value, 0.02) and average intensity (p-value, 0.03). The OR for the highest exposure category of cumulative exposure in the last 15-years was OR 3.32 (95% CI 1.22 to 9.03). Conclusions The results show an association between occupational exposure to carbon black and lung cancer risk, and a significant dose-response relationship with increasing intensity. The most recent 15 years appear to be the most relevant time of exposure.

Objectives The International Agency for Research on Cancer identified “occupational exposure as a painter” as a cause of lung cancer. Identifying the specific causative agent(s) has been difficult since painters are exposed to mixtures of known and suspected carcinogens that change over time. Using a large pooled dataset, we evaluated the risk of lung cancer among painters by duration of employment and painting activity. Methods Detailed individual data on smoking were available for 16258 lung cancer cases (605 painters, 3.7%) and 19922 age- and sex-matched controls (473 painters, 2.4%) from SYNERGY, a pooled effort of 12 case-control studies in Europe and Canada. Painting activity was classified from job titles using ISCO 1968 and ISIC Revision 2 codes. Multivariable logistic regression models were adjusted for age, gender, centre, smoking habits and previous employment in high-risk occupations. Results An OR of 1.38 (95% CI 1.20 to 1.59) was found for ever working as a painter; the excess risk of lung cancer increased with increasing years of employment (p-trend Conclusions These findings support the evidence of an increased risk of lung cancer among painters. Analyses by painting activity may help to identify causative agents.

Objectives Several epidemiologic studies indicate an increased risk of lung cancer among cooks but it is not known whether this is caused by cigarette smoking or by occupational exposure to carcinogens. Emissions from high-temperature frying have been classified by the IARC as probably carcinogenic to humans. Methods We used data from the SYNERGY project with pooled information on lifetime work histories and tobacco smoking from 13 176 lung cancer cases and 16 129 controls from 11 case-control studies in Europe and Canada. There were 704 persons (405 men, 299 women) who had ever worked as a cook or kitchen worker (based on ISCO-68), among them 340 cases and 364 controls. ORs and 95% CIs were estimated by unconditional logistic regression, adjusted for study, age, sex, smoking, and ever employment in an occupation with established lung cancer risk. Results Occupation as a cook or kitchen worker was associated with an increased lung cancer risk before (OR 1.20, 95% CI 1.03 to 1.40) but not after (OR 1.01, 95% CI 0.86 to 1.20) controlling for smoking habits. There was no significant exposure-response relationship in terms of work duration, and no significant heterogeneity in lung cancer risk among cooks across studies. It was not possible to separate cooks from other kitchen workers. Conclusions Working as a cook or kitchen worker was not associated with an increased risk of lung cancer. However, the possible risk by cooking fumes cannot be ruled out. Misclassification of exposure may have biased our results towards the null.

“Occupational exposure as a painter” was classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC) based on increased risks of cancers of the lung, bladder, and mesothelioma. Painters are exposed to a mixture of known and suspected lung carcinogens; thus it has been difficult to identify the specific agent(s) contributing to the elevated risk of lung cancer. Although the exposure to occupational carcinogens could differ according to the job duties of a painter, it is unknown whether the risk of lung cancer differs according to the painter type. Data from the SYNERGY study were used to evaluate the risk of lung cancer associated with ever working as a painter, duration of employment, and type of painter (classified according to ISCO and ISIC codes). SYNERGY is a pooled effort of 11 case-control studies in European countries and Canada that includes detailed individual data on smoking for 13389 lung cancer cases and 16384 age- and sex-matched controls. Among the cases and controls, there were 462 and 383 painters, respectively. Multivariable unconditional logistic regression models were adjusted for age, gender, centre, tobacco pack-years, and occupational exposures to asbestos, silica, polycyclic aromatic hydrocarbons, chromium VI and nickel as assessed by a job-exposure matrix. An odds ratio (OR) of 1.31 (95% CI, 1.12-1.45) was associated with ever working as painter and the risk of lung cancer increased with increasing years of employment (p-value for trend = 0.0004). A similar magnitude of effect and trend with duration of employment was observed in construction painters (ISCO 93120/ISIC 5000) but not in automobile painters (ISCO 93960/ISIC 3843,9513). Results were similar when restricted to men but uninformative for women only due to small numbers. There was no significant difference in risk when stratified by histological type and restricted to never smokers. Painters, particularly in the construction industry, are at an increased risk for lung cancer and this risk increases with duration of employment. These results will be further refined by specific type of painter and by including additional studies to increase the precision of the risk estimates. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1877. doi:10.1158/1538-7445.AM2011-1877

“Occupational exposure as a hairdresser or barber” was classified as probably carcinogenic to humans by the International Agency for Research on Cancer in volume 99 (2010). Small increases in lung cancer risk (20-40%) are found in most cohort studies but without adequate adjustment for smoking. Studies in Scandinavia and the USA show a higher prevalence of smokers among hairdressers than in the general population. The SYNERGY project has pooled information on lifetime work histories (ISCO-68) and tobacco smoking from 13479 cases and 16350 controls, including 20% women, from 11 case-control studies in 12 European countries and Canada. The original studies were conducted between 1985 and 2005. Odds ratios (OR) for lung cancer and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusted for age, sex, study, cigarette pack-years and time since quitting smoking. Less than 1% of the study population had ever worked as hairdresser or barber (0.89% of cases and 0.74% of controls). Hairdressers and barbers experienced a slight increase in lung cancer risk OR 1.16 (95%CI 0.90-1.49), which disappeared after adjusting for smoking OR 0.97 (95%CI 0.73-1.30). Results by duration of employment showed highest risks in hairdressers with short employment. Results were similar by gender, histology of lung cancer, and for women hairdressers. We observed a slight and non-significant increase in risk for male barbers, particularly in barbers with the longest employment and after adjustment for smoking. We could not detect an association between having worked as hairdresser or barber and increased lung cancer risk overall after adjusting for smoking. However, among male barbers we observed an increasing risk with increasing duration, although non-significant, after adjusting for tobacco smoking. Final results will include several more studies, and thereby increase the precision of our effect estimates. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1875. doi:10.1158/1538-7445.AM2011-1875

Introduction: Diesel-motor exhaust (DME) is classified by IARC as probably carcinogenic to humans. The epidemiological evidence is evaluated as limited since many studies lack adequate information on tobacco smoking and only few studies reported on exposure-response relationships. Our objective is to investigate the risk of lung cancer following occupational exposure to DME, while controlling for smoking and potential occupational confounders. Methods: The SYNERGY project pooled information on lifetime work histories and tobacco smoking from more than 13300 cases and 16300 controls from case-control studies conducted in 12 European countries and Canada. A job exposure matrix based on ISCO codes, assigning no (0), low (1) or high (2) exposure to DME was applied to determine level of exposure to DME. Cumulative exposure was defined as: ∑(level2 * duration). Odds ratios (OR) of lung cancer and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusted for age, sex, study, pack-years and time since quitting smoking, and ever employment in a “Group A” job, i.e. occupations with established lung cancer risk. Results: Workers exposed to low levels of occupational DME exposure had an increased risk of lung cancer after 40 years of exposure OR 1.31 (95% CI 1.14-1.51), while workers exposed to high DME levels experienced a similar risk already after short duration ( Conclusion: Our results indicate that occupational exposure to DME is associated with an increased risk of lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3777.

Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], Β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10 73). Two 10q25 SNPs (rs1329650[G], Β = 0.367, s.e. = 0.059, P = 5.7 × 10 10; and rs1028936[A], Β = 0.446, s.e. = 0.074, P = 1.3 × 10 9) and one 9q13 SNP in EGLN2 (rs3733829[G], Β = 0.333, s.e. = 0.058, P = 1.0 × 10 8) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 × 10 8). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 × 10 8) was significantly associated with smoking cessation. © 2010 Nature America, Inc. All rights reserved.