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Projects / Programmes source: ARIS

Molecular epidemiology of asbestos-related diseases and new approaches for an early detection and treatment of mesothelioma

Research activity

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

Code Science Field
B680  Biomedical sciences  Public health, epidemiology 

Code Science Field
3.05  Medical and Health Sciences  Other medical sciences 
Keywords
asbestos, asbestosis, malignant mesothelioma, genetic polymorphism, genomics
Evaluation (rules)
source: COBISS
Researchers (5)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  05299  MSc Niko Arnerić  Public health (occupational safety)  Researcher  2010 - 2013  136 
2.  05279  MSc Rajko Črnivec  Public health (occupational safety)  Researcher  2010 - 2013  81 
3.  12218  PhD Metoda Dodič Fikfak  Public health (occupational safety)  Researcher  2010 - 2013  1,230 
4.  11711  PhD Vita Dolžan  Biochemistry and molecular biology  Head  2010 - 2013  765 
5.  23759  PhD Alenka Franko  Public health (occupational safety)  Researcher  2010 - 2013  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
Although asbestos-related diseases are among the most extensively studied occupational diseases and the causal relationship between asbestos exposure and asbestosis has been proved, relatively little is known about the genetic factors that may modify the individual's susceptibility to the development of these diseases. In line with the reports that asbestos stimulates the production of reactive oxygen species (ROS), upregulates inducible nitric synthase (iNOS) and activates inflammatory cascades, our previous studies have shown that genetic polymorphisms of some enzymes that detoxify ROS and their toxic products represent risk factors for developing asbestosis in workers occupationally exposed to asbestos. As many polymorphic enzymes are involved in oxidative stress defence and asbestos sensing, we aim to investigate the influence of genetic variability on the risk of developing asbestosis as well as malignant mesothelioma, one of the most severe and fatal diseases associated with asbestos exposure. Considering the long latency period and 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, the increase in cases of this aggressive tumour is not expected to stabilize before 2030 or even later. The aims of our current study are: to investigate the influence of polymorphisms in novel candidate genes on the risk for developing asbestosis; to investigate if the same genetic factors that influence the asbestosis risk also influence the risk for malignant mesothelioma; to perform the whole genome analysis to identify potential new genetic factors that influence the risk for malignant mesothelioma; to investigate the associations between asbestos exposure, genetic factors and the risk of developing asbestos-related diseases. Two case-control studies will be performed to accomplish our aims. In the first study, the cases will be defined as subjects with asbestosis presented at the State Board for the Recognition of Occupational Asbestos Diseases at the Clinical Institute of Occupational Medicine in Ljubljana, whereas in the second one, they will be defined as patients with mesothelioma of pleura or peritoneum, diagnosed at the Institute of Oncology in Ljubljana and the State Board for the Recognition of Occupational Asbestos Diseases at the Clinical Institute for Occupational, Traffic and Sports Medicine in Ljubljana. In both studies, the controls will be subjects occupationally exposed to asbestos who have also been presented at the State Board for the Recognition of Occupational Asbestos Diseases, but who have not developed any asbestos-related disease. Data on smoking and asbestos exposure will be obtained for all subjects. A blood sample for DNA isolation for genetic analyses will be obtained from every participant. Methods based on real time PCR (TaqMan assays) will be used to genotype functional polymorphisms in candidate genes. The whole genome analysis will be performed on high density SNP microarrays (Illumina 1M). Next, in silico analysis will be performed to screen for functional variants in the regions of interest and finally, genotyping methods that could be used in routine clinical practice will be introduced for the analysis of these functional variants (TaqMan and/or Caspar assays). To assess the associations between either asbestosis or mesothelioma, asbestos exposure, genotypes, and potential confounders and/or effect modifiers, the odds ratios (OR) and corresponding 95 % confidence intervals will be calculated using univariate logistic regression, followed by multivariate modelling. In our study, we expect to obtain data on the genetic susceptibility to asbestosis and malignant mesothelioma in subjects occupationally and/or environmentally exposed to asbestos. The results of the study will provide a basis for the development of new methods for earlier diagnosis and more effective treatment of asbestos-related diseases.
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. We obtained important novel data on the genetic susceptibility to malignant mesothelioma and asbestosis in subjects occupationally and/or environmentally exposed to asbestos. An important achievement are our findings that polymorphism of inducible nitric oxide synthase (iNOS) may 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 reactive oxygen species and nitric oxide and activates the inflammatory cascades. An outstanding scientific contribution of our research project is the finding of the causal relationships between genetic and environmental factors and asbestos-related diseases. The finding that genetic factors modify the relationship between cumulative exposure to asbestos and asbestosis will have a major impact on future research in the field of occupational / environmental diseases, because we have clearly shown that interactions between genetic and environmental factors have to be taken into account. We thus contributed significantly to a better understanding of gene – environmental interactions that will support the planning of more efficient approaches for active intervention in the pathogenetic mechanisms of asbestos disease in terms of disease prevention. Another achievment that is an important contribution both for science and for clinical practice is our observation that SMRPs levels are good markers for monitoring the course of disease and response to treatment with chemotherapy in patients with malignant mesothelioma. In the treatment of malignant mesothelioma, adverse events and toxicity on one hand and resistance resistance to the treatment with the selected anti-tumor agents on the other hand, represent a major problem . In our research project we also investigated pharmacogenetic polymorphisms in metabolic pathways and targets of the most commonly used drugs for chemotherapy of malignant mesothelioma, cisplatin and gemcitabine. We were the first in the world to identify some of the genetic polymorphisms in metabolic pathways of gemcitabine and cisplatin and in DNA repair that are associated with the risk for adverse reactions to treatment with these agents and influence the survival of malignant mesothelioma patients. Translation of these finding into clinical practice could contribute to a more effective treatment and better prognosis of these patients. A large amount of novel data on genetic factors that influence the risk of developing malignant mesothelioma and response to treatment is expected to emerge from the biostatistical analysis of our data obtained from our genome wide study of malignant mesothelioma. We believe that new findings obtained by the GWAS analysis will enable the development of new approaches to treatment.
Significance for the country
In Slovenia the incidence of asbestos related diseases is rapidly increasing. Since 1998 more than 2500 occupational asbestos-related diseases have been diagnosed in Slovenia. The fact that the incidence of malignant 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 12 months after diagnosis. Our study thus gained important new insights into the genetic predisposition for the development of asbestosis and malignant mesothelioma in people who were professionally and/or environmentally exposed to asbestos. We have identified serum markers that allow early detection of disease progression and evaluation of tumor response to the treatment. New diagnostic and prognostic markers both at the candidate gene level and at the whole genome level will allow for more effective treatment and improved survival of patients with malignant mesothelioma.
Most important scientific results Annual report 2010, 2011, 2012, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2010, 2011, 2012, final report, complete report on dLib.si
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