Review
Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases

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Abstract

Exposure to asbestos fibers is a major risk factor for malignant pleural mesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on α1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes.

Introduction

Exposure to asbestos fibers is a well-known risk factor for malignant pleural mesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques.

Different mechanisms of damage caused by asbestos fibers have been identified or hypothesized. Inhaled asbestos fibers penetrate the lung epithelium and irritate the pleural cell lining, causing repeated cycles of damage, repair and local inflammation. This repeated scratching may lead to the formation of plaques or to mesothelioma. Another possible mechanism could occur when asbestos fibers interfere with the mitosis. The damages caused to the mitotic spindle could potentially lead to aneuploidy or induce the other typical chromosome anomalies often found in mesothelioma [1].

Asbestos toxicity and carcinogenicity may be mediated by reactive oxygen or nitrogen species (ROS/RNS). This mechanism, activated by the interaction of asbestos fibers with the mesothelial cells and from the prolonged phagocytic activity of inflammatory cells, is probably the most circumstantiated one [1], [2]. The free radicals generated by these processes may cause cellular toxicity and carcinogenicity by inducing lipid peroxidation, altering signal transduction pathways, and damaging the DNA directly [3]. Consequences of oxidative damage include single strand breaks and DNA base modification [4]. Furthermore, asbestos-induced DNA damage has been demonstrated to activate tyrosine kinase (TK) both in lung epithelium and in mesothelial cells [5]. In addition, asbestos fibers induce phosphorylation of the mitogen-activated protein kinases and extra cellular signal-regulated kinases 1 and 2 and elevate expression of early response proto-oncogenes (FOS or JUN or activator protein 1 family members) [6], [7], [8], [9].

In the last decade the role of genetic polymorphism in the pathogenesis of cancer and other diseases has been the object of intensive research. Many studies have focused on polymorphic genes active in various steps of xenobiotic and oxidative metabolism, or in DNA repair processes.

Even though mesothelioma has been considered for many years the paradigm of environmentally determined cancers, the presence of a genetic component in the etiology of this disease has been hypothesized, mostly based on the evidence that only a minority of asbestos exposed subjects develop MPM (5–17% of individuals heavily exposed). This consideration, together with the frequent reports of MPM familial clustering [10], [11], suggested a role of genetic susceptibility also in this disease. Similar arguments have been carried out also for other asbestos-mediated diseases, both neoplastic, like lung cancer, and non-neoplastic (e.g., asbestosis, pleural plaques).

In this paper, we will review published studies addressing the association between diseases linked to asbestos and genetic polymorphisms. The relevance of genetic factors in explaining the pathogenesis of these diseases will be discussed, with a special focus on MPM.

Section snippets

Bibliographic search

The search for papers was performed using the PubMed database (National Library of Medicine, National Institutes of Health, Bethesda, MD, USA—http://www.ncbi.nlm.nih.gov/PubMed) and it was updated up to January 31, 2008. Specific keywords (Mesh terms[mesh]) and free texts terms (words in title or abstract field[tiab]) were used as a search strategy. The first group of terms referred to main concepts related to genetic polymorphisms (polymorphism, genetic[mesh] OR genotype[mesh] as keywords, and

Genetic polymorphism and non-neoplastic diseases associated to asbestos exposure

Eight studies evaluated the role of genetic polymorphisms in non-neoplastic diseases associated to asbestos exposure (Table 1). All these studies were conducted in the framework of occupationally exposed subjects (maximum number of subjects: 639 [12], [13]). The most common disease was asbestosis, but pleural abnormalities have been investigated as well. Polymorphic genes were genotyped by PCR and restriction enzyme-based methods.

Genetic polymorphism and exposure to asbestos in lung cancer

Asbestos is a well-known risk factor for lung cancer, although in case–control studies this exposure is frequently not included in the set of risk factors. Eight articles estimating the risk associated to asbestos exposure and the effect modification induced by genetic polymorphism are illustrated in Table 2. The most frequent study design was case–control, but the case-only approach has been used as well. All the genotypes were obtained by PCR and by methods based on restriction enzymes.

Genetic polymorphism and MPM

Asbestos exposure is the main risk factor for MPM, a rare and aggressive tumor. MPM is characterized by a poor prognosis and it is scarcely influenced by current therapies, as shown by a median survival from presentation of 9–12 months [1]. Seven published articles report on the risk of MPM in association with genetic polymorphism: three from Finland [14], [22], [30] and four from Italy [31], [32], [33], [34]. The Italian studies were conducted in two areas with high MPM incidence, due to

Biorepositories as a tool for studying genetic susceptibility to MPM: two Italian experiences

Biomarker studies require processing and storage of numerous biological samples with the goals of obtaining a large amount of information and minimizing future research costs. An efficient study design includes original samples processing provisions, such as cryopreservation, DNA isolation, and specimens preparation for subsequent analysis. This approach is necessary especially when the studied condition is rare and biological samples are collected over a long period of time. To address the

Discussion

Although the role of asbestos as a direct cause of MPM, lung cancer, asbestosis and other respiratory tract diseases is well established, it has been hypothesized that the effect of asbestos exposure may be modified by genetic polymorphisms, and a number of studies explored this issue.

Future directions

In conclusion, although the published studies are based on relatively low numbers of subjects, their results suggest that some genetic polymorphisms may modify the risk of MPM and other neoplastic and non-neoplastic diseases caused by exposure to asbestos fibers. In particular, the evidence from polymorphisms of genes involved in oxidative stress and DNA repair seems more circumstantiated. Studies in larger panels of patients and controls are necessary to confirm preliminary data.

Nowadays,

Acknowledgments

This study was supported by grants funded by Associazione Italiana per la Ricerca sul Cancro (AIRC), “Ricerca Sanitaria Finalizzata della Regione Piemonte” and Fondazione Buzzi-Unicem per la Ricerca sul Mesotelioma.

References (48)

  • A. Xu et al.

    Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: implication from mutation patterns induced by reactive oxygen species

    Environ. Health Perspect.

    (2002)
  • D.W. Kamp et al.

    The molecular basis of asbestos induced lung injury

    Thorax

    (1999)
  • B.T. Mossman et al.

    Oxidants and signaling by mitogen-activated protein kinases in lung epithelium

    Am. J. Respir. Cell Mol. Biol.

    (2006)
  • C.B. Manning et al.

    A mutant epidermal growth factor receptor targeted to lung epithelium inhibits asbestos-induced proliferation and proto-oncogene expression

    Cancer Res.

    (2002)
  • J. Li et al.

    Effect of platelet-derived growth factor on the development and persistence of asbestos-induced fibroproliferative lung disease

    J. Environ. Pathol. Toxicol. Oncol.

    (2004)
  • J. Subramanian et al.

    Lung cancer in never smokers: a review

    Clin. Oncol.

    (2007)
  • P.T. Cagle et al.

    Differential diagnosis of benign and malignant mesothelial proliferations on pleural biopsies

    Arch. Pathol. Lab. Med.

    (2005)
  • V. Ascoli et al.

    Mesothelioma in blood related subjects: report of 11 clusters among 1954 Italy cases and review of the literature

    Am. J. Ind. Med.

    (2007)
  • C.M. Smith et al.

    Inherited glutathione-S-transferase deficiency is a risk factor for pulmonary asbestosis

    Cancer Epidemiol. Biomark. Prev.

    (1994)
  • K.T. Kelsey et al.

    The glutathione S-transferase theta and mu deletion polymorphisms in asbestosis

    Am. J. Ind. Med.

    (1997)
  • A. Hirvonen et al.

    Glutathione S-transferase and N-acetyltransferase genotypes and asbestos-associated pulmonary disorders

    J. Natl. Cancer Inst.

    (1996)
  • A. Franko et al.

    Glutathione S-transferases GSTM1 and GSTT1 polymorphisms and asbestosis

    J. Occup. Environ. Med.

    (2007)
  • A. Horská et al.

    Genetic predisposition and health effect of occupational exposure to asbestos

    NeuroEndocrinol. Lett.

    (2006)
  • K. Jakobsson et al.

    Genetic polymorphism for glutathione-S-transferase mu in asbestos cement workers

    Occup. Environ. Med.

    (1994)
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