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

Our plain-English summary of Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases, by M. Neri, D. Ugolini, I. Dianzani, et al (Mutation Research, 2008).

The study

• Authors: M. Neri, D. Ugolini, I. Dianzani, F. Gemignani, S. Landi, A. Cesario, C. Magnani, L. Mutti, R. Puntoni, S. Bonassi
• Journal: Mutation Research
• Published: 2008;659(1-2):126-36
• Type of article: Review
• Cited by: 53 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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 alpha1-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.

In plain English

This article was a review, not a new study. The authors searched PubMed up to January 31, 2008, for studies giving a numerical estimate of the link between inherited gene variants (polymorphisms) and asbestos-related diseases: malignant pleural mesothelioma (MPM), lung cancer, asbestosis and pleural abnormalities. Of 159 citations found, 24 papers describing 19 studies were included. In the reviewed studies, the GSTM1 'null' genotype tended to go with higher risks. The authors counted two lung cancer and two MPM studies where this was statistically significant, but some of these results were for subgroups or gene combinations; in one Finnish MPM study, GSTM1 null alone had p = 0.06. Results for GSTT1 and SOD2 were inconsistent or conflicting. MPM data came from fewer than 250 patients in three areas, and no gene was consistently linked to MPM risk. One Italian study from Casale Monferrato found raised risks with variants of DNA repair genes XRCC1 and XRCC3. The authors noted small study sizes, differing exposure assessment and multiple comparisons as limitations. They concluded that some gene variants may modify asbestos-related disease risk and that larger studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published studies retrieved from the PubMed database
• Who was studied: 24 papers describing 19 studies, selected from 159 PubMed citations (search updated to January 31, 2008). The studies were of asbestos-exposed people with MPM, lung cancer, asbestosis or pleural abnormalities, and of comparison groups, in countries including the USA, Finland, Italy, Sweden, Slovenia, Slovakia, Spain, China, Turkey and the UK.
• Exposure: Asbestos exposure, mostly occupational (for example asbestos cement plant workers, insulators and carpenters). Fiber types were not specified. The gene variants studied were in genes of xenobiotic and oxidative metabolism and DNA repair, such as GSTM1, GSTT1, NAT2, SOD2, EPHX, CYP1A1, XRCC1, XRCC3, alpha1-antitrypsin and MPO.
• Main results:
  • In the discussion, the authors wrote that the GSTM1 null genotype was associated with increased risks across the reviewed studies, especially in highly exposed subjects. They counted statistical significance in two lung cancer studies and two MPM studies, but not in a pooled lung cancer analysis. Some of these significant results were for subgroups or gene combinations rather than GSTM1 null alone. In one of the lung cancer studies, the exposure was to carcinogens other than smoking, including asbestos.
  • In a Finnish study of 44 mesothelioma patients compared with 270 blood donors, GSTM1 null alone had an OR of 1.8 (95% CI 1.0 to 3.5, p = 0.06), and NAT2 slow acetylator status had an OR of 2.1 (95% CI 1.1 to 4.1, p = 0.03).
  • In that Finnish study, the combined GSTM1 null and NAT2 slow acetylator genotypes had an OR of 3.6 (95% CI 1.3 to 10.2, p = 0.006).
  • In a small Turkish case-only lung cancer study, GSTM1 null subjects with a history of exposure to carcinogens other than smoking, including asbestos, had an 8-fold higher risk.
  • Studies of the GSTT1 null genotype gave inconsistent results.
  • In a Spanish study of 100 people with asbestosis, Pi*Z heterozygotes (an alpha1-antitrypsin variant) had a higher risk of asbestosis than exposed controls from the same plant: OR 8.9 (95% CI 1.02 to 76.4). The reviewers noted that the allele is rare, so its contribution to overall asbestosis risk is limited.
  • In a US lung cancer case-control study, people who were asbestos-exposed and had the G/G genotype in the MPO promoter had an OR of 1.7 (95% CI 1.1 to 2.7), compared with unexposed G/G subjects.
  • Published MPM data came from fewer than 250 patients in three study areas. No association with MPM risk was consistently shown for metabolism or DNA repair genes.
  • An Italian study of 81 MPM patients and 110 matched controls from Casale Monferrato found an association between MPM and variants in XRCC1 and XRCC3.
  • In that Casale Monferrato study, risk genotypes of XRCC3 T241M had an OR of 4.1 (95% CI 1.3 to 13.2), and risk genotypes of XRCC1 R399Q had an OR of 2.1 (95% CI 1.08 to 4.3).
  • Finnish and Italian MPM studies found associations with the same SOD2, EPHX and NAT2 variants, but in opposite directions. The authors said this could be due to chance given the small numbers.
• The authors' conclusion: The authors concluded that, although the studies were based on relatively low numbers of subjects, their results suggest that some genetic polymorphisms may modify the risk of MPM and other asbestos-related diseases. They said larger studies are needed to confirm the preliminary data.
• Limitations the authors state:
  • The reviewed studies had small sample sizes, especially for MPM and non-neoplastic diseases.
  • Exposure assessment differed between studies, and most counted only occupational exposure.
  • The studies differed in how controls were selected.
  • In lung cancer studies, it may be difficult to separate the role of asbestos from that of other carcinogens such as tobacco smoke.
  • Multiple comparisons can produce false-positive results.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Lung Cancer, Pleural Plaques, Etiology, Reactive Oxygen Species (ROS).

Related studies

• Genetic susceptibility to malignant mesothelioma and exposure to asbestos: the influence of the familial factor — D. Ugolini, M. Neri, et al. (2008)
• Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure — M. Neri, R. Filiberti, et al. (2005)
• Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes — M.K. Kukkonen, S. Hämäläinen, et al. (2011)
• Pooled analysis of NAT2 genotypes as risk factors for asbestos-related malignant mesothelioma — M. Betti, M. Neri, et al. (2009)
• Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study — G. Matullo, S. Guarrera, et al. (2013)
• Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma — S. Landi, F. Gemignani, et al. (2007)

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