Metabolic genotypes as modulators of asbestos-related pleural malignant mesothelioma risk: A comparison of Finnish and Italian populations

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Abstract

The role of CYP1A1, GSTM1, GSTT1, EPHX1, and NAT2 genotypes in susceptibility to malignant mesothelioma (MM) was compared in two case-control studies, previously conducted in two countries where different types of asbestos fibers have been used [Hirvonen et al., 1995. Inherited GSTM1 and NAT2 defects as concurrent risk modifiers in asbestos-related human malignant mesothelioma. Cancer Res. 55, 2981–2983; Hirvonen et al., 1996. Glutathione S-Transferase and N-Acetyltransferase genotypes and asbestos-associated pulmonary disorders. J. Natl. Cancer Inst.88, 1853–1856; Neri et al., 2005. Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure. Mutat. Res. 592, 36–44]. Fifty-seven asbestos-exposed MM patients and 255 controls were recruited in Italy, 48 cases and 121 controls in Finland. In order to make the two studies comparable, they have been updated and new genotyping analyses have been performed. The NAT2 fast acetylator and EPHX1 low-activity genotypes were positively associated with MM in the Italian study, while they were negatively associated with this malignancy in the Finnish one. A combined significant effect was also observed in the Italian study for the NAT2 fast acetylator and EPHX1 low-activity genotypes, while this combination was protective in the Finnish study. Combination of NAT2 fast acetylator and GSTM1 null genotype posed a significantly increased risk of MM in the Italian, but not in the Finnish study. The opposite results obtained in Finland and Italy may be ascribed to random chance, but a role may be hypothesized for the fact that different types of asbestos have been used in the two countries.

Introduction

The incidence of pleural malignant mesothelioma (MM) is high in some areas of Northern Italy (e.g., in Genoa and La Spezia), due to both environmental and occupational exposure to asbestos fibers (Gennaro et al., 2005). MM incidence rates are rising in Europe, although a deceleration has started in some countries (Montanaro et al., 2003; Peto et al., 1999). One challenge in preventing this rapidly lethal tumor lies in the early identification of factors that increase the individual risk of cancer. Asbestos is the main risk factor for MM, with 80% of all patients reporting a previous exposure to this agent. Both direct and indirect biological mechanisms are involved in asbestos-induced carcinogenesis, including generation of reactive free radicals as a result of the interaction between fibers and the target cells (Kamp and Weitzman, 1999). The distribution of fiber lengths differs according to the types of asbestos fibers (for example between anthophyllite and other amphibole fibers), as shown by the concentrations of asbestos bodies in bronchoalveolar lavage (Karjalainen et al., 1996). Differences in asbestos fibers’ length are known to modify their biopersistence, surface properties and their interaction with cellular oxidative metabolism (Riganti et al., 2003).

Many polymorphic metabolic genes encode enzymes involved in conjugation and detoxification of environmental or endogenous toxicants, and modify individual cancer risk (Snyder and Hong, 2004; Vineis et al., 1999).

Previous studies have shown that both malignant and nonmalignant asbestos-related diseases develop more frequently in asbestos-exposed subjects carrying homozygous deletion (null genotype) of GSTM1 gene (Neri et al., 2005; Hirvonen et al., 1995, Hirvonen et al., 1996; Smith et al., 1994). In highly exposed Finnish workers, the GSTM1 deletion in combination with the NAT2 slow acetylator genotype was associated with a remarkably increased risk of mesothelioma (Hirvonen et al., 1995, Hirvonen et al., 1996). We have examined and compared the relationship between metabolic gene polymorphisms and mesothelioma in asbestos-exposed subjects in two studies conducted in Italy and in Finland, two countries known to have had occupational exposures to different types of asbestos fibers.

Section snippets

Study populations

The case-control study performed in Finland was previously described (Hirvonen et al., 1995, Hirvonen et al., 1996), and included 48 asbestos exposed MM subjects enrolled between 1985 and 1993 from the Helsinki University Central Hospital, and 121 controls from a cohort of construction workers who were recruited for a health screening survey at the Finnish Institute of Occupational Health.

For the Italian study, 80 MM patients were enrolled at the time of diagnosis in the pneumologic departments

Discussion

While it has been clearly established that exposure to asbestos fibers is the major risk factor for MM, the biochemical and cellular mechanisms leading from exposure to disease are not well understood. Reactive oxygen species (ROS) and oxidized cellular components have been hypothesized to play a role in MM etiology (Kamp and Weitzman, 1999; Kane, 1996).

Although asbestos itself is not a substrate for metabolic processes, associations between certain metabolic gene variants and MM have been

Acknowledgments

We are indebted with Lucia Benfatto, Monica Bianchelli, Valerio Gennaro, Anna Lazzarotto and Fabio Montanaro of the Mesothelioma Registry of the Liguria Region. This work was supported by the EU funded ECNIS network of excellence, by the Italian Ministry of Health and by “Fondazione ONLUS-Buzzi”. The work of MN was partially supported by AIRC (Italian Association for Cancer Research).

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