Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites - Neuroimaging results from the WELDOX II study.

OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. MATERIAL AND METHODS: GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson's disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). RESULTS: The median shift exposure to respirable Mn and Fe in active welders was 23µg/m3 and 110µg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(ß)=0.87, p<0.01) and choline (exp(ß)=0.84, p=0.04). R2* was positively associated with glutamate-glutamine and negatively with myo-inositol. CONCLUSIONS: Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations.

NOTCH1, HIF1A and other cancer-related proteins in lung tissue from uranium miners--variation by occupational exposure and subtype of lung cancer.

BACKGROUND: Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners. METHODOLOGY/PRINCIPAL FINDINGS: Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r(s)). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r(s) = 0.18, 95% CI 0.02-0.33; arsenic: r(s) = 0.23, 95% CI 0.07-0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%. CONCLUSIONS/SIGNIFICANCE: These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.

Association between lymph node silicosis and lung silicosis in 4,384 German uranium miners with lung cancer.

This study investigates the association between lymph node-only and lung silicosis in uranium miners with lung cancer and exposure to quartz dust. Tissue slides of 4,384 German uranium miners with lung cancer were retrieved from an autopsy archive and reviewed by 3 pathologists regarding silicosis in the lungs and lymph nodes. Cumulative exposure to quartz dust was assessed with a quantitative job-exposure matrix. The occurrence of silicosis by site was investigated with regression models for exposure to quartz dust. Miners with lung silicosis had highest cumulative quartz exposure, followed by lymph node-only silicosis and no silicosis. At a cumulative quartz exposure of 40 mg/m(3) × years, the probability of lung silicosis was above 90% and the likelihood of lymph node-only silicosis and no silicosis do not differ anymore. The results support that lymph node silicosis can precede lung silicosis, at least in a proportion of subjects developing silicosis, and that lung silicosis strongly depends on the cumulative quartz dose.

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners.

OBJECTIVE: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. METHODS: A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. RESULTS: There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. CONCLUSION: These results indicate a cell type characteristic effect of arsenic in the development of lung cancer.

A study on lung cancer mortality related to radon, quartz, and arsenic exposures in German uranium miners.

Between 1946 and 1990 uranium mining was undertaken on a large scale in East Germany. This study evaluates the proportional lung cancer risk of German uranium miners from radon, quartz, and arsenic exposure during mining operations at the WISMUT Corporation. The database of the WISMUT tissue repository and a comprehensive job-exposure matrix were used to compare exposure levels of lung cancer cases with deaths from diseases of the circulatory system for risk analysis. In addition, the ratio of lung cancer cases was compared to cases from diseases of the circulatory system to the corresponding ratio in the general population. The proportional lung cancer mortality of German uranium miners was 2.9-fold higher than in the general population of East Germany. Cumulative radon, quartz, and arsenic exposure were determined as risk factors for lung cancer among German uranium miners, where silicosis modified the risk of cumulative radon and quartz exposure. Silicotics were exposed to higher levels of quartz, radon, and arsenic than nonsilicotics. Because selection of the study population was based on a tissue repository, the results need to be interpreted with caution.

Role of exposure to radon and silicosis on the cell type of lung carcinoma in German uranium miners.

BACKGROUND: In East Germany, uranium mining was undertaken on a large scale from 1946 to 1990. Poor working conditions led to a high level of exposure to ionizing radiation and quartz dust. This analysis evaluates the histopathology of lung carcinoma in uranium miners in relation to radon exposure and silicosis. METHODS: A database developed for autopsy cases ascertained in a pathological tissue repository of German uranium miners was used to estimate odds ratios for developing lung carcinoma by major cell type with regard to radon exposure and silicosis. Silicosis information was extracted from autopsy protocols. Working level months (WLM) were calculated with a job-exposure matrix to assess lifetime radon exposure. Risk estimates were based on 3414 male miners who died from small cell lung carcinoma (SCLC, n = 1446), squamous cell carcinoma (SqCC, n = 1006), or adenocarcinoma (AC, n = 962) between 1957 and 1990. RESULTS: SCLC and SqCC seem more likely to be associated with high radon exposure than AC. Mean cumulative radon exposure was 868 (SD 631) WLM in SCLC, 871 (SD 652) WLM in SqCC, and 743 (SD 598) WLM in AC. Silicosis prevalence was 26% in SCLC, 38% in SqCC, and 30% in AC. In silicotics, AC and SqCC had a relatively higher frequency at the expense of SCLC. SCLC occurred earlier than AC and SqCC. CONCLUSION: High radon exposure was associated with a higher relative frequency of SCLC and SqCC than AC. Silicosis tended to increase the appearance of SqCC and AC.