ATM gene mutations in former uranium miners of SDAG Wismut: a pilot study.

Ataxia-telangiectasia is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. Heterozygous carriers of an ataxia-telangiectasia gene mutation are predisposed to epithelial cancers. We initiated a study to elucidate the frequency and clinical relevance of ATM gene mutations in former uranium miners exposed to high levels of radiation from radon and its decay products. Former uranium miners with Schneeberg lung cancer (n=48), former uranium miners suffering from silicosis (n=60) and uranium miners without occupational lung disorders (n=102) were investigated for nine mutations in the ATM gene. One gastric and one prostate cancer occurred in the group of miners without occupational lung diseases. Mutation analyses for S707P, IVS10-6Tright curved arrow G, 2250Gright curved arrow A, E1978X, R2443X, 3801delG, S49C and D2625E-A2626P were performed using genomic DNA obtained from peripheral blood samples. Three ATM gene alterations (S707P, S49C or IVS10-6Tright curved arrow G) were observed. Of all cancer patients, 8.0% were heterozygous, but only 1.9% of the non-cancer controls were [OR=4.6; 95% confidence interval (CI), 0.8-26.8]. In this pilot study a major role of six ATM gene mutations could not be revealed for cancer predisposition in former uranium miners. The results leave the possibility of a moderate risk associated with more subtle ATM gene alterations.

A fuzzy-classifier using a marker panel for the detection of lung cancers in asbestosis patients.

BACKGROUND: The aim of this study was to evaluate the diagnostic power of a fuzzy classifier and a marker panel (CYFRA 21-1, NSE, CRP) for the detection of lung cancers in comparison to asbestosis patients at high-risk of developing lung cancer. PATIENTS AND METHODS: A panel of four tumour markers, i.e. CEA, CYFRA 21-1, NSE, SCC and CRP, was measured in newly diagnosed lung cancer patients of different histological types and stages in comparison to asbestosis patients. In this prospective study, a fuzzy classifier was generated with the data of 216 primary lung cancer patients and 76 patients suffering from asbestosis. The patients and controls were recruited in the clinics of the University in Giessen. RESULTS: At 95%-specificity, it was possible with this tool to detect non-small cell lung cancers in 70% at stage I (n = 30), in 95% at stage II (n = 22), in 98% at stage III (n = 56), in 92% at stage IV (n = 50) and small cell lung cancers with limited disease status (n = 21) in 90.7% and with extensive disease status (n = 37) in 97.3%. In contrast, single markers had a detection rate significantly far below these. The application of the classifier was examined on an independent collective of 38 non-small cell lung cancers and 76 asbestosis patients. The latter underwent stationary rehabilitation in the clinics for occupational diseases in Bad Reichenhall or Falkenstein. The fuzzy classifier showed correct negative classification in 75 out of the 76 cancer-free asbestosis patients, which confirmed a specificity of 97.4%. The overall sensitivity for lung cancer detection in high risk populations was 73.6%. All large cell carcinomas were detected. The positive predictive value was 77.7%. The negative predictive value reached 94.8%. CONCLUSION: With the fuzzy classifier and a marker panel, a reliable diagnostic tool for the detection of lung cancers in a high risk population is available.

How conflicted authors undermine the World Health Organization (WHO) campaign to stop all use of asbestos: spotlight on studies showing that chrysotile is carcinogenic and facilitates other non-cancer asbestos-related diseases.

The silicate mineral asbestos is categorized into two main groups based on fiber structure: serpentine asbestos (chrysotile) and amphibole asbestos (crocidolite, amosite, anthophyllite, tremolite, and actinolite). Chrysotile is used in more than 2 000 applications and is especially prevalent in the construction industry. Although its use is banned or restricted in more than 52 countries, an estimated 107 000 workers die from asbestos exposure each year, and approximately 125 million workers continue to be exposed. Furthermore, ambient exposures persist to which the public is exposed, globally. Today, the primary controversies regarding the use of asbestos are the potencies of different types of asbestos, as opposed whether or not asbestos causes morbidity and mortality. The asbestos industry has promoted and funded research based on selected literature, ignoring both clinical and scientific knowledge. In this piece, we highlight a prominent example of a conflicted publication that sought to undermine the World Health Organization (WHO) campaign to stop the use of all forms of asbestos, including chrysotile asbestos. Independent and rigorous scientific data provide sufficient evidence that chrysotile asbestos, like other forms of asbestos, is a cause of asbestos-related morbidity and premature mortality.

GSTM1, GSTT1, and GSTP1 polymorphism and lung cancer risk in relation to tobacco smoking.

The impact of genetic polymorphisms in GSTM1, GSTP1 or GSTT1 on susceptibility to lung cancer has received particular interest since these enzymes play a central role in detoxification of major classes of tobacco carcinogens. In the current German study we investigated the role of GSTM1, GSTT1 and GSTP1 polymorphisms as a genetic modifier of risk for individuals with lung cancer as susceptible genotypes especially in relation to tobacco smoking. The GSTM1, the GSTP1 as well as GSTT1-polymorphism were determined by real time PCR analysis in 446 lung cancer patients and 622 controls. The observed allele frequencies of the GSTP1 polymorphism in the population were within the range described for Caucasians. Multivariate analyses of lung cancer patients, who carried at least one mutant variant allele of GSTP1 (OR=1.03; 95%-CI: 0.76-1.39) did not show any elevated risks. GSTM1 or GSTT1 null-genotypes were found in 47.3% resp. 18.5% of the controls and in 52.5% resp. 16.8% of the cancer patients. The estimated risk of the GSTM1 null genotype for lung cancer was OR=1.34 (95%-CI: 0.99-1.81) and for the GSTT1 null genotype OR=0.88 (95%-CI: 0.59-1.32). When analyzed by histology no individual subtype of lung cancer was strongly associated with the polymorphisms. Lung cancer risk rose significantly with higher cumulative cigarette consumption confirming the association with smoking-related lung cancer risk. Stratified analysis between tobacco smoking and variant genotypes revealed for heavy smokers (>60 pack-years) increasing risks at the presence for at least one copy of the GSTP1 variant allele OR=50.56 (95%-CI: 15.52-164.79). The corresponding risks for GSTM1 null genotypes were OR=112.08 (95%-CI: 23.02-545.71) and for the GSTT1 null-genotype OR=158.49 (95%-CI: 17.75-1415.06) in smokers >60 pack-years. Analysing the interaction between tobacco smoking and the genotypes, combined smoking and having the susceptible genotypes did not show a joint effect. In this study polymorphisms of the GSTM1, GSTT1 or GSTP1 had no relevant modifying effect on lung cancer risk and cumulative smoking dose.

After Helsinki: a multidisciplinary review of the relationship between asbestos exposure and lung cancer, with emphasis on studies published during 1997-2004.

Despite an extensive literature, the relationship between asbestos exposure and lung cancer remains the subject of controversy, related to the fact that most asbestos-associated lung cancers occur in those who are also cigarette smokers: because smoking represents the strongest identifiable lung cancer risk factor among many others, and lung cancer is not uncommon across industrialised societies, analysis of the combined (synergistic) effects of smoking and asbestos on lung cancer risk is a more complex exercise than the relationship between asbestos inhalation and mesothelioma. As a follow-on from previous reviews of prevailing evidence, this review critically evaluates more recent studies on this relationship--concentrating on those published between 1997 and 2004--including lung cancer to mesothelioma ratios, the interactive effects of cigarette smoke and asbestos in combination, and the cumulative exposure model for lung cancer induction as set forth in The Helsinki Criteria and The AWARD Criteria (as opposed to the asbestosis-->cancer model), together with discussion of differential genetic susceptibility/resistance factors for lung carcinogenesis by both cigarette smoke and asbestos. The authors conclude that: (i) the prevailing evidence strongly supports the cumulative exposure model; (ii) the criteria for probabilistic attribution of lung cancer to mixed asbestos exposures as a consequence of the production and end-use of asbestos-containing products such as insulation and asbestos-cement building materials--as embodied in The Helsinki and AWARD Criteria--conform to, and are further consolidated by, the new evidence discussed in this review; (iii) different attribution criteria (e.g., greater cumulative exposures) are appropriate for chrysotile mining/milling and perhaps for other chrysotile-only exposures, such as friction products manufacture, than for amphibole-only exposures or mixed asbestos exposures; and (iv) emerging evidence on genetic susceptibility/resistance factors for lung cancer risk as a consequence of cigarette smoking, and potentially also asbestos exposure, suggests that genotypic variation may represent an additional confounding factor potentially affecting the strength of association and hence the probability of causal contribution in the individual subject, but at present there is insufficient evidence to draw any meaningful conclusions concerning variation in asbestos-mediated lung cancer risk relative to such resistance/susceptibility factors.

Pulmonary fibrosis following household exposure to asbestos dust?

An 81-year-old woman was dying from histologically confirmed pulmonary fibrosis without having had any asbestos exposure in the workplace. The lung dust fibre analysis showed significantly increased "asbestos bodies" (AB) (2,640 AB per gram of wet lung tissue) and asbestos fibre concentrations (8,600,000 amphibole fibres of all lengths and 540,000 amphibole fibres with a length ≥5 µm per gram of dry lung tissue). Asbestos exposure was revealed to have occurred during household contact after 27 years of washing her husband's industrial clothing that had been contaminated by asbestos at his workplace in an asbestos textile factory. Household asbestos dust exposure as a risk or co-factor in the aetiology of the fatal pulmonary fibrosis is discussed.

CYP1A1 and CYP1B1 Polymorphism and Lung Cancer Risk in Relation to Tobacco Smoking.

BACKGROUND: The impact of genetic polymorphisms in CYP1A1 or CYP1B1 on susceptibility to lung cancer has received particular attention since these enzymes play a central role in the activation of major classes of tobacco carcinogens. Several polymorphisms in the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. In the current German study, we investigated the role of CYP1A1 and CYP1B1 polymorphisms as a genetic modifier of risk for individuals with lung cancers as susceptible genotypes, especially in relation to tobacco smoking. MATERIALS AND METHODS: Three polymorphisms, the CYP1A1 T6235C (CYP1A1 MspI), the CYP1A1 A4889G-position (CYP1A1 iva) as well as the CYP1B1 codon 432 polymorphism were determined by real-time PCR analysis in 446 lung cancer patients and in 622 controls. RESULTS: The observed allele frequencies in the population were within the range described for Caucasians. Multivariate analyses of lung cancer patients, who carried at least one mutant variant allele of CYP1A1 T6235C (OR=1.06; 95%-CI: 0.7-1.6), CYP1A1 A4889G (OR=1.09; 95%-CI: 0.63-1.88) or CYP1B1 Val432Leu (OR=1.01 CI: 0.73-1.39) did not show any elevated risks. When analysed by histology, no individual subtype of lung cancer was significantly associated with the polymorphisms. Lung cancer risk rose significantly with higher cumulative cigarette consumption. Stratified analysis between tobacco smoking and variant genotypes revealed, for heavy smokers (>60 pack-years), increasing risks with the presence of at least one copy of the CYP1A1 T6235C variant allele OR=27.74 (95%-CI: 4.34-177.25), the CYP1A1 A4889G position OR=33.23 (95%-CI: 3.11-354.99) and the CYP1B1 OR=418.70 (95%-CI: 45.45-3856.89). By analysing the interaction between tobacco smoking and the genotypes, the combination of smoking and having the susceptible genotypes did not show a joint effect. CONCLUSION: In this study polymorphism of the CYP1A1 T6235C- or A4889G-position as well as CYP1B1-codon 432-polymorphisms had no relevant modifying effect on lung cancer risk and cumulative smoking dose.