Isabelle Stücker

Effect of Occupational Exposures on Lung Cancer Susceptibility: A Study of Gene–Environment Interaction Analysis

Background: Occupational exposures are known risk factors for lung cancer. Role of genetically determined host factors in occupational exposure–related lung cancer is unclear. Methods: We used genome-wide association (GWA) data from a case–control study conducted in 6 European countries from 1998 to 2002 to identify gene–occupation interactions and related pathways for lung cancer risk. GWA analysis was performed for each exposure using logistic regression and interaction term for genotypes, and exposure was included in this model. Both SNP-based and gene-based interaction P values were calculated. Pathway analysis was performed using three complementary methods, and analyses were adjusted for multiple comparisons. We analyzed 312,605 SNPs and occupational exposure to 70 agents from 1,802 lung cancer cases and 1,725 cancer-free controls. Results: Mean age of study participants was 60.1 ± 9.1 years and 75% were male. Largest number of significant associations (P ≤ 1 × 10−5) at SNP level was demonstrated for nickel, brick dust, concrete dust, and cement dust, and for brick dust and cement dust at the gene-level (P ≤ 1 × 10−4). Approximately 14 occupational exposures showed significant gene–occupation interactions with pathways related to response to environmental information processing via signal transduction (P < 0.001 and FDR < 0.05). Other pathways that showed significant enrichment were related to immune processes and xenobiotic metabolism. Conclusion: Our findings suggest that pathways related to signal transduction, immune process, and xenobiotic metabolism may be involved in occupational exposure–related lung carcinogenesis. Impact: Our study exemplifies an integrative approach using pathway-based analysis to demonstrate the role of genetic variants in occupational exposure–related lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 24(3); 570–9. ©2015 AACR.

Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies

Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age‐adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8–143.2) for SqCC, 111.3 (95% CI: 69.8–177.5) for SCLC and 21.9 (95% CI: 16.6–29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5–124.6), 108.6 (95% CI: 50.7–232.8) and 16.8 (95% CI: 9.2–30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.

CYP1A1 T3801 C polymorphism and lung cancer: A pooled analysis of 2,451 cases and 3,358 controls

CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen; it is therefore conceivable that genetically determined variations in its activity modify individual susceptibility to lung cancer. The role of the CYP1A1 MspI polymorphism in lung cancer has been widely studied but has not been fully clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis of 22 case‐control studies on CYP1A1 and lung cancer risk. We found a clear association between the CYP1A1 homozygous MspI restriction fragment length polymorphism (RFLP) and lung cancer risk in Caucasians (age‐ and gender‐adjusted odds ratio = 2.36; 95% confidence interval 1.16–4.81); other associations were weaker or not statistically significant. The association with the homozygous variant was equally strong for squamous cell carcinomas and adenocarcinomas among Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects with the MspI RFLP combined variants (homozygotes plus heterozygotes), the increase in the risk of lung cancer was steeper than among the individuals with the homozygous reference allele. Our analysis suggests that Caucasians with homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The data were more consistent among Caucasians, with a strong association between the homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a stronger association in men than in women. The analyses were more inconsistent and failed to reach statistical significance in Asians. This observation might be due to design specificities or unknown effect modifiers in the Asian studies.

Exposure to Diesel Motor Exhaust and Lung Cancer Risk in a Pooled Analysis from Case-Control Studies in Europe and Canada

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 from 13,304 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 never-smokers, 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 and subgroup analyses.

Pooled analysis of the CYP1A1 exon 7 polymorphism and lung cancer (United States).

Objective: Cytochrome P450 1A1 plays a major role in the bioactivation of a number of tobacco procarcinogens. Much interest has focused on a polymorphism in exon 7 of the CYP1A1 gene which has been associated with a more inducible form of the enzyme. However, past results of its association with lung cancer have been inconsistent, especially in Caucasians. We carried out a pooled analysis of the data submitted to the Genetic Susceptibility to Environmental Carcinogens (GSEC) database to further investigate this association and, especially, to examine the modifying effects of smoking status and race. Methods: The data set used in this analysis included 11 studies and a total of 1950 cases and 2617 controls. Both fixed- and random-effects, meta-analysis models were used to investigate heterogeneity among studies. Because no clear heterogeneity was found, a pooled analysis was conducted using unconditional logistic regression. Results: The pooled odds ratio for subjects heterozygous and homozygous for the exon 7 polymorphism was 1.15 (95% confidence interval: 0.95–1.39) and 1.54 (95% CI: 0.97–1.46), respectively (p for gene-dosage effect: 0.03). This association was stronger for squamous cell carcinoma (SCC) than adenocarcinoma, and appeared to be stronger in Caucasians than Asians (p for interaction: 0.03). Statistically significant interactions were also detected for smoking status and sex, with the effect of the polymorphism being stronger in never-smokers and in females. Conclusions: The present data suggest that the CYP1A1 exon 7 polymorphism may confer an increased risk of lung cancer, particularly of SCC, and especially in never-smokers and in women. These interactions need to be confirmed when additional studies are available for pooling.

International Lung Cancer Consortium: Pooled Analysis of Sequence Variants in DNA Repair and Cell Cycle Pathways

Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3081–9)

Polycyclic aromatic hydrocarbons and fatal ischemic heart disease.

Background: Several toxicologic and epidemiologic studies have produced evidence that occupational exposure to polycyclic aromatic hydrocarbons (PAH) is a risk factor for ischemic heart disease (IHD). However, a clear exposure–response relation has not been demonstrated. Methods: We studied a relation between exposure to PAH and mortality from IHD (418 cases) in a cohort of 12,367 male asphalt workers from Denmark, Finland, France, Germany, Israel, The Netherlands and Norway. The earliest follow up (country-specific) started in 1953 and the latest ended in 2000, averaging 17 years. Exposures to benzo(a)pyrene were assessed quantitatively using measurement-driven exposure models. Exposure to coal tar was assessed in a semiquantitative manner on the basis of information supplied by company representatives. We carried out sensitivity analyses to assess potential confounding by tobacco smoking. Results: Both cumulative and average exposure indices for benzo(a)pyrene were positively associated with mortality from IHD. The highest relative risk for fatal IHD was observed for average benzo(a)pyrene exposures of 273 ng/m3 or higher, for which the relative risk was 1.64 (95% confidence interval = 1.13–2.38). Similar results were obtained for coal tar exposure. Sensitivity analysis indicated that even in a realistic scenario of confounding by smoking, we would observe approximately 20% to 40% excess risk in IHD in the highest PAH-exposure categories. Conclusions: Our results lend support to the hypothesis that occupational PAH exposure causes fatal IHD and demonstrate a consistent exposure–response relation for this association.

Collection of Human Genomic DNA From Buccal Cells for Genetics Studies: Comparison Between Cytobrush, Mouthwash, and Treated Card

Alternative sources such as buccal cells have already been tested for genetic studies and epidemiological investigations. Thirty-seven volunteers participated in this study to compare cytology brushes, mouthwash, and treated cards for DNA collection. Quantity and quality of DNA and cost and feasibility were assessed. The mean DNA yield at 260 nm was found to be 3.5, 4, and 2.6 μg for cytobrushes, mouthwashes, and treated cards, respectively. A second quantification technique by fluorescence showed differences in the DNA yield with 1.1 and 5.2 μg for cytobrushes and mouthwash, respectively. All buccal samples allowed isolation of DNA suitable for polymerase chain reaction. According to the procedure of sample collection, the yield and purity of collected DNA, and storage conditions, the use of cytobrush appears to be the more appropriate method for DNA collection. This protocol has been validated and is currently applied in three large-scale multicentric studies including adults or children.

Increased risk of lung cancer in individuals with a family history of the disease: A pooled analysis from the International Lung Cancer Consortium

BACKGROUND AND METHODS Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analysed. Unconditional logistic regression models and generalised estimating equations were used to estimate odds ratios and 95% confidence intervals. RESULTS Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in the risk of lung cancer, after adjustment for smoking and other potential confounders (95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (odds ratios (OR) = 1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR = 1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR = 1.44, 95% CI: 1.07, 1.93), after adjustment. CONCLUSIONS The occurrence of lung cancer among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those risks associated with cigarette smoking. While the role of genetic variation in the aetiology of lung cancer remains to be fully characterised, family history assessment is immediately available and those with a positive history represent a higher risk group.

Investigation of occupational and environmental causes of respiratory cancers (ICARE): a multicenter, population-based case-control study in France

BackgroundOccupational causes of respiratory cancers need to be further investigated: the role of occupational exposures in the aetiology of head and neck cancers remains largely unknown, and there are still substantial uncertainties for a number of suspected lung carcinogens. The main objective of the study is to examine occupational risk factors for lung and head and neck cancers.Methods/designICARE is a multi-center, population-based case-control study, which included a group of 2926 lung cancer cases, a group of 2415 head and neck cancer cases, and a common control group of 3555 subjects. Incident cases were identified in collaboration with cancer registries, in 10 geographical areas. The control group was a random sample of the population of these areas, with a distribution by sex and age comparable to that of the cases, and a distribution by socioeconomic status comparable to that of the population. Subjects were interviewed face to face, using a standardized questionnaire collecting particularly information on tobacco and alcohol consumption, residential history and a detailed description of occupational history. Biological samples were also collected from study subjects. The main occupational exposures of interest are asbestos, man-made mineral fibers, formaldehyde, polycyclic aromatic hydrocarbons, chromium and nickel compounds, arsenic, wood dust, textile dust, solvents, strong acids, cutting fluids, silica, diesel fumes, welding fumes. The complete list of exposures of interest includes more than 60 substances. Occupational exposure assessment will use several complementary methods: case-by-case evaluation of exposure by experts; development and use of algorithms to assess exposure from the questionnaires; application of job-exposure matrices.DiscussionThe large number of subjects should allow to uncover exposures associated with moderate increase in risks, and to evaluate risks associated with infrequent or widely dispersed exposures. It will be possible to study joint effects of exposure to different occupational risk factors, to examine the interactions between occupational exposures, tobacco smoking, alcohol drinking, and genetic risk factors, and to estimate the proportion of respiratory cancers attributable to occupational exposures in France. In addition, information on many non-occupational risk factors is available, and the study will provide an excellent framework for numerous studies in various fields.