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Projects / Programmes source: ARIS

Molecular epidemiology of asbestos related diseases and screening test for early detection of mesothelioma

Research activity

Code Science Field Subfield
3.08.00  Medical sciences  Public health (occupational safety)   

Code Science Field
B690  Biomedical sciences  Occupational health, industrial medicine 
Keywords
molecular epidemiology, pharmacogenetics, asbestosis, mesothelioma, occupational diseases
Evaluation (rules)
source: COBISS
Researchers (5)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  03079  PhD Katja Breskvar  Biochemistry and molecular biology  Researcher  2007  189 
2.  05279  MSc Rajko Črnivec  Public health (occupational safety)  Researcher  2007 - 2009  81 
3.  12218  PhD Metoda Dodič Fikfak  Public health (occupational safety)  Researcher  2007 - 2009  1,230 
4.  11711  PhD Vita Dolžan  Biochemistry and molecular biology  Head  2007 - 2009  765 
5.  23759  PhD Alenka Franko  Public health (occupational safety)  Researcher  2007 - 2009  386 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  77,780 
2.  0381  University of Ljubljana, Faculty of Medicine  Ljubljana  1627066  48,446 
Abstract
A. Asbestos-related diseases are among the most extensively studied occupational diseases and the causal relationship between asbestos exposure and asbestosis has been well established. However, relatively little is known about the genetic factors that might modify the individual susceptibility to the development of this disease. Many studies suggest that reactive oxygen and nitric species may be involved in the pathogenesis of asbestos-related diseases. Asbestos fibres stimulate the production of reactive oxygen species and also upregulate the inducible nitric oxide synthase (iNOS). Specific enzyme systems (dismutases such as MnSOD; catalase and glutathione S-transferases such as GSTM1, GSTT1, GSTP1) that detoxify reactive oxygen and nitric species are present in the cells. Inherited polymorphisms of genes coding for MnSOD, catalase, glutathione S-transferases of different classes and iNOS lead to inter-individual variability in the capacity of detoxification of these reactive species. One of the aims of our study is to investigate whether the genetic polymorphisms of MnSOD, catalase, glutathione S-transferases GSTM1, GSTT1, GSTP1 and/or iNOS represent risk factors for the development of asbestos-related diseases in workers occupationally exposed to asbestos. We expect to identify genetic polymorphisms that increase the risk of the development of asbestos-related diseases. This would enable to identify those subjects exposed to asbestos who are specially susceptible to the development of asbestos-related diseases and to prepare guidelines for the regular follow up of these subjects. These measures would contribute to an early detection of asbestos-related diseases, especially lung cancer and malignant mesothelioma. B. Malignant mesothelioma is a highly aggressive, incurable tumour of serosal cavities caused mainly by asbestos exposure. The incidence of mesothelioma in Slovenia is increasing. With the conventional diagnostic methods malignant mesothelioma is usually diagnosed in an advanced stage of the disease when the treatment is not effective, therefore new methods for an early detection of this disease are searched for. The aim of our study is also to investigate whether the method of measuring soluble mesothelin related protein (SMR) in the serum is a sufficiently specific and sensitive screening method for an early detection of mesothelioma and in which phase of the disease process this marker becomes positive. If the method of measuring SMR in serum proves to be highly specific and sensitive we shall suggest that it should be introduced as a screening test into a regular programme for an early detection of mesothelioma in subjects exposed to asbestos and thus enable more effective treatment and better prognosis of this disease.
Significance for science
Considering that relatively little was known about genetic afctors that may modify individual susceptibility to the development of the asbestos-related diseases, the results of our study represent an important contribution to the development of science on the worldwide scale. An important achievement are our findings that polymorphism of metabolic genes involved in the detoxification of reactive oxygen species (ROS) and their toxic products modify the risk for asbestosis in workers, occupationaly exposed to asbestos. Our results are in concordance with previouly published observations that asbestos stimulates the production of ROS and nitroc oxide (NO) and activates the inflammatory cascades. An important novel finding of our study was that GSTT1 gene deletion may have a protective effect on the development of asbestosis. Our results are consistent with the reports of a protective effect of GSTT1-null genotype on lung cancer, as asbestosis is known to be associated with an increased risk of lung cancer. Similar to some previous studies, we did not observe any association between asbestosis and GSTM1-null genotype. We were also the first in the world to report that GSTP1 genotype coding for an enzyme with a high conjugation capacity increases the risk of developing asbestosis by 50 %. Another key finding of our study was that the MnSOD –9Ala/Ala genotype increases the risk of asbestosis. In our study we also observed a slightly elevated risk of asbestosis for the CAT -262 TT genotype associated with a lower catalytic activity of catalase. We were also the first in the world to report a slightly, although not significantly higher risk of asbestosis in subjects with a higher number of CCTTT repeats in the promoter of inducible NO synthase (iNOS). The data on possible genetic predisposition for developing of asbestos related diseases in people exposed to asbestos are crucial for determining groups that are especially at risk. The improved understanding of the genetic factors affecting the pathogenetic mechanisms of the asbestos-related diseases may also provide a basis for earlier diagnosis of these diseases and new therapeutic approaches.
Significance for the country
The incidence of asbestos related diseases in Slovenia is rapidly increasing. Since 1998 more than 2500 occupational asbestos-related diseases have been diagnosed in Slovenia. The fact that the incidence of mesothelioma, the most fatal of all asbestos related disease, in Slovenia raised exponentially in the period from 1994 to 2002 raises concern. Due to the long latency period, the increase in new cases of mesothelioma is not expected to stabilize earlier than between 2025 and 2030 if we consider the fact that the consumption of asbestos in Slovenia reached its peak in the mid-1980s and that asbestos was banned by law in 1996. Malignant asbestos-related diseases, such as lung cancer and mesothelioma, are usually diagnosed very late, therefore the survival time is short. The analysis of a cohort from the asbestos-cement factory (the highest number of workers exposed to asbestos in Slovenia) showed that the survival of workers with mesothelioma was approximately 17 months after diagnosis. The data on the interaction of genetic predisposition and exposure to asbestos and smoking will help to identify exposed workers at increased risk of the development of asbestosis which is known to be associated with an increased risk of lung cancer and asbestos-related cancers. The identification of a genetic marker of the increased risk of asbestos-related diseases enables us to propose the guidelines for screening programmes so that workers at risk could be monitored more frequently and the asbestos-related cancer could be diagnosed earlier. A particulary important achievement of the project is the introduction of the method for measuring soluble mesothelin related protein (SMR) in the serum that allows early detection of the progression of malignant mesothelioma as well as monitoring the response to treatment. Because of the expected increase in the incidence of mesothelioma and a short survival time of mesothelioma patients, this method is extremely important for a more effective treatment and a better prognosis of this disease.
Most important scientific results Annual report 2008, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2008, final report, complete report on dLib.si
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