Autopsy indicators of exposure to asbestos and lung cancer

In many instances, only post-mortem examination can provide probative data about (i) the presence of lung cancer and (ii) its relationship to exposure to asbestos. Moreover, the results of an autopsy may suggest that a thorough investigation of occupational history should be carried out, since such information is rarely recorded in clinical records. We considered pathological indicators for selecting subjects who had a high likelihood of previous occupational exposure to asbestos. The positive predictive value of pleural plaques ranged from 20 to 75%, depending on their size and on the concentrations of asbestos bodies and uncoated mineral fibres in the lung. The probability of no exposure was greater than 90% if neither asbestos bodies nor uncoated mineral fibres were found. Another purpose of our work on lung cancer and exposure to asbestos was to investigate the relationships between exposure and the occurrence of specific cell types of lung cancer in an autopsied population. Both work history and asbestos body count were considered. The matched analysis showed some tendency towards an association between the occurrence of adenocarcinoma and the presence of indicators of exposure to asbestos.     

Smoking status,occupational asbestos exposure and bronchial location of lung cancer

The objective of this study was to determine the factors associated with central airway versus peripheral bronchial location of lung cancer. All patients diagnosed with lung cancer from 1997 through 2000 in the Respiratory Disease Department of Rouen University Hospital were prospectively interviewed about their smoking and occupational history using a standardized questionnaire. All patients underwent white-light bronchial endoscopy using a 4.5 mm flexible endoscope. Tumors were classified as central when they were accessible and visible using this technique. Out of 217 cases of lung cancer included in this study, 155 (71%) were central. Histological type of lung cancer was strongly associated with bronchial location as central location was observed in 48, 82 and 92% of Adenocarcinoma (AC), Squamous Cell (SqC), and Small Cell Carcinoma (SCC), respectively (P<0.0001). Among non asbestos-exposed patients, location varied little with smoking status, with central location frequency ranging from 74 to 80%. In contrast, lung cancer was recorded central in 41% of long-term (> or =10 years) ex-smokers, 67% of short-term (<10 years) ex-smokers and 75% of current smokers (P=0.04) among patients exposed to asbestos, suggesting an interaction between duration of smoking cessation and occupational asbestos exposure with respect to lung cancer location. These findings were confirmed after adjustment for sex, age and histologic type in multivariate analysis. These results suggest that individually-tailored multimodality screening strategies relying on various combinations of low-dose CT scan, sputum analysis and fluorescence endoscopy according to each patient's profile may be more effective than standard strategies based on a single approach for all patients.     

Peroxiredoxins and tropomyosins as plasma biomarkers for lung cancer and asbestos exposure

The prognosis of lung cancer is poor due to late diagnosis, the lack of established screening programs, and the paucity of early biomarkers for high-risk populations. Plasma proteome analysis was used to identify novel biomarkers for diagnosing lung cancer, and to unravel the mechanisms of underlying pathogenesis. Plasma proteins obtained from asbestos-exposed lung cancer cases detected by CT screening, asbestos-exposed subjects, clinical lung cancer patients, and healthy tobacco smokers, 5-6 cases in each group, were separated by two-dimensional gel electrophoresis, and identified with tandem mass spectrometry (LC-MS/MS). Nine proteins were selected for immunological confirmation in a test or validation set of plasma samples from an additional 49 clinical lung cancer cases, 66 asbestos-exposed patients, and 107 healthy tobacco smokers. Twenty-eight unique proteins were differentially expressed between the four study groups (p<0.05). Peroxiredoxin 1 (PRX1) was detected as a novel plasma marker for lung cancer (p=0.001). We also confirmed the previously found association of serum amyloid A with lung cancer (p<0.001). High plasma levels of tropomyosin 4 (TPM4: p<0.001) and peroxiredoxins 1 and 2 (PRX2: p<0.001) correlated with asbestos exposure or a diagnosis of asbestosis. PRX1 and PRX2 exhibited an inverse correlation with tobacco smoking (p<0.001). Plasma peroxiredoxins 1 and 2, and tropomyosin 4 were shown to associate with asbestos-exposure, and peroxiredoxin 1 with lung cancer. High plasma levels of peroxiredoxin 1 may result from genetic damage caused by reactive oxygen species. This study has identified several biomarkers worthy of further investigation in lung cancer and asbestos-related diseases.     

Clinical evaluation of primary lung cancer induced by exposure to asbestos

Upon autopsy, asbestos was found in the lungs of 7 primary lung cancer patients out of 70. These seven-patients were men over 60 years old. All of them had occupational histories of exposure to asbestos. In histological classification, 4 of the cases were adenocarcinoma and the others were squamous. Six of them were in the peripheral area. According to chest X-rays two of the patients showed lung fibrosis (asbestosis), and all of them showed pleural plaque. Thus, we concluded that ten percent of the primary lung cancer cases autopsied in our hospital might be induced by exposure to asbestos.     

Genome-wide gene-environment interaction analysis for asbestos exposure in lung cancer susceptibility

Asbestos exposure is a known risk factor for lung cancer. Although recent genome-wide association studies (GWASs) have identified some novel loci for lung cancer risk, few addressed genome-wide gene-environment interactions. To determine gene-asbestos interactions in lung cancer risk, we conducted genome-wide gene-environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using our published Texas lung cancer GWAS dataset. This dataset included 317 498 SNPs from 1154 lung cancer cases and 1137 cancer-free controls. The initial SNP-level P-values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models with adjustment for age, sex, smoking status and pack-years. The P-value for the most significant SNP rs13383928 was 2.17×10(-6), which did not reach the genome-wide statistical significance. Using a versatile gene-based test approach, we found that the top significant gene was C7orf54, located on 7q32.1 (P = 8.90×10(-5)). Interestingly, most of the other significant genes were located on 11q13. When we used an improved gene-set-enrichment analysis approach, we found that the Fas signaling pathway and the antigen processing and presentation pathway were most significant (nominal P < 0.001; false discovery rate < 0.05) among 250 pathways containing 17 572 genes. We believe that our analysis is a pilot study that first describes the gene-asbestos interaction in lung cancer risk at levels of SNPs, genes and pathways. Our findings suggest that immune function regulation-related pathways may be mechanistically involved in asbestos-associated lung cancer risk.     

Histologic typing of lung cancer in Louisiana

To determine whether histologic patterns differed in the high- and low-lung cancer mortality parishes (counties) of Louisiana and whether the findings in the state differed from those in other parts of the United states, we studied the available histopathologic materials for 272 persons of the 815 who died of lung cancer in ten southern, nonurban Louisiana parishes during a seven-year period from 1971-1977. Squamous-cell carcinoma and small-cell anaplastic carcinoma were the most common tumor types, closely followed in frequency by adenocarcinoma, confirming reports by other investigators of a change during the past decade in the prevalence of various histopathologic types of lung cancer. The distribution of histopathologic types was not different for high- and low-mortality parishes but differed significantly from other areas of the U. S. Three persons had diagnoses consistent with pleural mesothelioma. Occupational histories obtained from relatives showed that one of those persons was a homemaker and the other two were sugarcane farmers with no discernable exposure to asbestos.     

Evaluation of primary multiple cancer manifesting exposure to asbestos

Twenty five cases (71%) of 35 primary multiple cancer, confirmed by autopsy, were proved to have been exposed to asbestos. Of these cases, lung and stomach cancers, which were related to the asbestos exposure, were main component of the multiple cancers. Thirteen of these cases had definite occupational histories of asbestos exposure and the number of asbestos bodies in five grams of autopsied wet lung tissue amounted to more than 1000. This result suggests that asbestos exposure might possibly induce a high incidence of multiple cancers.     

Survival in operable non-small-cell lung cancer: role of p53 mutations, tobacco smoking and asbestos exposure

Validated markers are needed to identify operable lung cancer patients with poor prognosis. About one-half of non-small-cell lung cancers (NSCLCs) carry a mutation in the p53 tumor-suppressor gene. We examined 101 NSCLC patients for surgical stage, completeness of resection, tobacco smoking, asbestos exposure, age, gender and p53 gene mutations as prognostic factors after a follow-up period of 4 years. Cox's multivariate regression model was applied to quantify the associations with overall and cancer-related survival. Patients with a wild-type p53 gene had an overall 4-year survival of 43% and those with a mutated p53 gene, 35%. In squamous-cell carcinoma, stage and heavy smoking, defined as the median of pack-years smoked, had prognostic significance for overall survival. Only stage was associated with poor cancer-related survival. Asbestos exposure was not associated with overall survival or cancer-related survival in squamous-cell carcinoma or adenocarcinoma. In adenocarcinoma, p53 mutation, in addition to stage, emerged as a significant predictor of poor cancer-related survival.     

The molecular epidemiology of asbestos and tobacco in lung cancer

Asbestos is a well-known toxin and lung carcinogen. Epidemiologic studies have established tobacco smoke and asbestos exposures synergistically interact to enhance lung cancer risk. The biologic mechanism responsible for this interaction has been the subject of considerable debate. Studies have suggested that asbestos may act as a carcinogen by generating free radical and reactive oxygen species, by inducing tissue injury and subsequent cellular growth, via large-scale chromosome loss and by enhancing delivery of tobacco carcinogens to the respiratory epithelium. Recent molecular epidemiologic approaches further suggest that asbestos enhances the mutagenicity of tobacco carcinogens and that it acts, at least in part, independent of the tissue damage responsible for fibrosis.     

DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure

Five to seven percent of lung tumours are estimated to occur because of occupational asbestos exposure. Using cDNA microarrays, we have earlier detected asbestos exposure-related genomic regions in lung cancer. The region at 2p was one of those that differed most between asbestos-exposed and non-exposed patients. Now, we evaluated genomic alterations at 2p22.1-p16.1 as a possible marker for asbestos exposure. Lung tumours from 205 patients with pulmonary asbestos fibre counts from 0 to 570 million fibres per gram of dry lung, were studied by fluorescence in situ hybridisation (FISH) for DNA copy number alterations (CNA). The prevalence of loss at 2p16, shown by three different FISH probes, was significantly increased in lung tumours of asbestos-exposed patients compared with non-exposed (P=0.05). In addition, a low copy number loss at 2p16 associated significantly with high-level asbestos exposure (P=0.02). Furthermore, 27 of the tumours were studied for allelic imbalances (AI) at 2p22.1–p16.1 using 14 microsatellite markers and also AI at 2p16 was related to asbestos exposure (P=0.003). Our results suggest that alterations at 2p16 combined with other markers could be useful in diagnosing asbestos-related lung cancer.     

Mesothelioma and asbestos fiber type. Evidence from lung tissue analyses

Lung tissue samples from 78 cases from autopsy of mesothelioma in Canada, 1980 through 1984, and from matched referents were examined by optical and analytical transmission electron microscopic study. Concentrations of amosite, crocidolite, and tremolite fibers, and of typical asbestos bodies discriminated sharply between cases and referents. The distributions of chrysotile and anthophyllite/talc fibers and of all other natural and man-made inorganic fibers (greater than or equal to 8 microns) in the two series were quite similar. Relative risk was related to the concentration of long (greater than or equal to 8 microns) amphibole fibers with no additional information provided by shorter fibers. The proportion of long fibers was much higher for amphiboles than chrysotile and, except for chrysotile, systematically higher in cases than referents. Amphibole asbestos fibers could explain most mesothelioma cases in Canada and other inorganic fibers, including chrysotile, very few. Fibrous tremolite, contaminant of many industrial minerals including chrysotile, probably explained most cases in the Quebec mining region and perhaps 20% elsewhere.     

Long-term mortality from pleural and peritoneal cancer after exposure to asbestos: Possible role of asbestos clearance

Models based on the multistage theory of carcinogenesis predict that the rate of mesothelioma increases monotonically as a function of time since first exposure (TSFE) to asbestos. Predictions of long-term mortality (TSFE >or= 40 years) are, however, still untested, because of the limited follow-up of most epidemiological studies. Some authors have suggested that the increase in mesothelioma rate with TSFE might be attenuated by clearance of asbestos from the lungs. We estimated mortality time trends from pleural and peritoneal cancer in a cohort of 3,443 asbestos-cement workers, followed for more than 50 years. The functional relation between mesothelioma rate and TSFE was evaluated with various regression models. The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalized to include a term representing elimination over time. We observed 139 deaths from pleural and 56 from peritoneal cancer during the period 1950-2003. The rate of pleural cancer increased during the first 40 years of TSFE and reached a plateau thereafter. In contrast, the rate of peritoneal cancer increased monotonically with TSFE. The model allowing for asbestos elimination fitted the data better than the traditional model for pleural (p = 0.02) but not for peritoneal cancer (p = 0.22). The risk for pleural cancer, rather than showing an indefinite increase, might reach a plateau when a sufficiently long time has elapsed since exposure. The different trends for pleural and peritoneal cancer might be related to clearance of the asbestos from the workers' lungs.     

Occupational exposure and lung cancer risk

The importance of occupation held longest as a risk factor for lung cancer was examined in a prospective study in Norway of 11,995 men, among whom 125 cases occurred in a follow-up from 1966 through 1978. Based on information about occupation held longest, the respondents were classified into 3 groups according to suspected exposure to respiratory carcinogens at the workplace. After stratification for age, place of residence and cigarette smoking, we found a highly significant relative risk of 2.6 for those judged to have experienced definite exposure versus the group with no workplace exposure. The apparent risk-enhancing effect of occupational exposure was observed for all histologic subtypes. Stratification including a socioeconomic factor score led to a moderate reduction in the relative risk estimate. High risk estimates still obtained, however, for a limited number of occupations, the highest for workers in the mining and quarrying industries. Although the interpretation of the observed effect associated with a crude index of occupational exposure may be difficult, our results suggest that between 13 and 27% of the lung cancer cases observed among Norwegian men in the relevant time period can be attributed to harmful work-place exposure.