Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure

Our plain-English summary of Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure, by M. Neri, R. Filiberti, E. Taioli, et al (Mutation Research, 2005).

The study

• Authors: M. Neri, R. Filiberti, E. Taioli, S. Garte, V. Paracchini, C. Bolognesi, P.A. Canessa, V. Fontana, G.P. Ivaldi, A. Verna, S. Bonassi, R. Puntoni
• Journal: Mutation Research
• Published: 2005;592(1-2):36-44
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pleural malignant mesothelioma (MM) is a rare but extremely aggressive cancer. The limited impact of standard therapeutic treatments on survival rates makes the identification of factors that increase the individual risk a leading priority. The high proportion of cases explained by exposure to asbestos has guided intervention policies to an effective ban of this compound from our environment. However, MM cannot be solely attributed to this agent, and the role of predisposing factors and their interaction with asbestos exposure is increasingly studied. The role of mEH, GSTM1, GSTT1, NAT2, and CYP1A1 genotypes in modulating susceptibility to MM was examined in a case-control study of 80 subjects with a confirmed diagnosis of MM and 255 controls. Subjects with low mEH activity showed a significantly increased risk of MM (OR, 2.51; 95% CI, 1.11-5.68). The association was stronger in the group with low asbestos exposure (OR, 7.83; 95% CI, 0.98-62.60). A significant increased risk of MM was also found in NAT2 fast acetylators (OR, 1.74; 95% CI, 1.02-2.96). The presence of synergisms between genotypes, i.e., mEH and NAT2 (LRT for heterogeneity p<0.023), mEH and GSTM1 (LRT p<0.061), and NAT2 and GSTM1 (LRT p<0.049), combined with the interaction observed with exposure to asbestos, suggests the presence of gene-environment and gene-gene interactions in the development of MM, although the size of the study group does not allow to draw clearcut conclusions. Since genetic polymorphisms can also modify the extent of genetic damage occurring in subjects exposed to carcinogens, we measured the frequency of micronuclei in peripheral blood lymphocytes of a subgroup of MM cases. The limited number of cases (28) did not allow to observe significant effects. In conclusion, these results strengthen the hypothesis that individual susceptibility to MM can be modulated by the interaction between polymorphic genes involved in the metabolism and the intensity of asbestos exposure.

In plain English

This Italian case-control study asked whether inherited variants of five chemical-processing genes (mEH, GSTM1, GSTT1, NAT2, CYP1A1) were linked to pleural malignant mesothelioma. It compared 80 patients diagnosed 1996 to 2003 with 255 healthy Northern Italian controls. Patients were grouped by likely asbestos exposure: 57 with high probability (mostly shipyard workers) and 23 with low probability. Compared with high predicted mEH activity, low activity carried higher odds of mesothelioma (odds ratio 2.51, 95% confidence interval 1.11 to 5.68), as did NAT2 'fast' versus 'slow' acetylators (1.74, 1.02 to 2.96). Comparing low-exposure patients with all controls, odds ratios against high mEH activity were 6.63 (0.83 to 52.97) for intermediate and 7.83 (0.98 to 62.60) for low activity; these wide intervals included 1.0. Some combinations had higher odds ratios: NAT2 fast acetylator plus low mEH activity, versus slow acetylator plus high activity, gave 4.36 (1.62 to 11.79). Tests of chromosome damage (micronuclei) in blood cells of 28 patients showed no statistically significant differences. The authors concluded these genes may influence susceptibility, especially mEH, but urged caution because the study was small.

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: Case-control study of genetic polymorphisms, with a micronucleus (chromosome damage) test in a subgroup of cases
• Who was studied: 80 patients with confirmed pleural malignant mesothelioma, diagnosed 1996 to 2003 and recruited from three units in Genoa and Sarzana (La Spezia), Italy, and 255 healthy population controls recruited in 1999 in Northern Italy as part of a study on cardiovascular disease
• Exposure: Asbestos exposure estimated by Mesothelioma Registry staff from interviews and registry data. Patients were classed as high probability of exposure (57, mostly shipyard workers) or low probability (23). Fiber types were not specified. Genotypes studied: mEH, GSTM1, GSTT1, NAT2 and CYP1A1.
• Main results:
  • All patients compared with controls: NAT2 fast acetylator genotype versus slow acetylator (reference), OR 1.74 (95% CI 1.02 to 2.96)
  • All patients compared with controls: low predicted mEH activity versus high activity (reference), OR 2.51 (95% CI 1.11 to 5.68)
  • All patients compared with controls: intermediate mEH activity versus high activity, OR 2.16 (95% CI 0.96 to 4.87). The test for linear trend across mEH activity groups gave p less than 0.04.
  • No other polymorphism was significantly associated with MM. GSTM1 null subjects, compared with GSTM1 functional, had a 48% increased risk, which was not statistically significant (OR 1.48, 95% CI 0.86 to 2.54).
  • Highly exposed patients compared with controls: the NAT2 fast acetylator association, against slow acetylators, appeared confined to this group, OR 2.14 (95% CI 1.15 to 3.98)
  • Low-exposure patients compared with controls, against high mEH activity: ORs were 6.63 (95% CI 0.83 to 52.97) for intermediate activity and 7.83 (95% CI 0.98 to 62.60) for low activity. Both confidence intervals include 1.0.
  • Only 1 of the 23 low-exposure patients had the high-activity mEH genotype
  • Combination of NAT2 fast acetylator and low mEH activity, against NAT2 slow acetylator with high mEH activity (reference): OR 4.36 (95% CI 1.62 to 11.79)
  • Combination of GSTM1 null and low mEH activity, against GSTM1 functional with high mEH activity (reference): OR 3.70 (95% CI 1.37 to 10.01). The combination of NAT2 fast acetylator with GSTM1 null genotype was also statistically significant (LRT p less than 0.049).
  • Smoking did not modify the genotype results (data not shown)
  • Micronucleus test in 28 patients: micronucleus frequency was higher in younger, female and less exposed patients, but none of these differences reached statistical significance
• The authors' conclusion: The authors concluded that metabolic gene polymorphisms involved in oxidation processes may have a role in individual susceptibility to MM, especially mEH. They concluded that the interactions with NAT2 genotype and with asbestos exposure level need further study in larger groups.
• Limitations the authors state:
  • The small sample size calls for caution in interpreting the results
  • The lack of association between micronucleus frequency and the polymorphisms is inconclusive because statistical power was low
  • Controls were significantly younger than cases and included fewer males. The authors argued this was unlikely to affect the risk estimates.
  • Because of technical difficulties, mEH exon 3 data were available for only 101 controls

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Asbestos Exposure, Case-Control Study, Micronuclei.

Related studies

• Genetic susceptibility to malignant mesothelioma and exposure to asbestos: the influence of the familial factor — D. Ugolini, M. Neri, et al. (2008)
• Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes — M.K. Kukkonen, S. Hämäläinen, et al. (2011)
• Metabolic genotypes as modulators of asbestos-related pleural malignant mesothelioma risk: a comparison of Finnish and Italian populations — M. Neri, E. Taioli, et al. (2006)
• Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases — M. Neri, D. Ugolini, et al. (2008)
• Role of NAT2 deficiency in susceptibility to lung cancer among asbestos-exposed individuals — S.T. Saarikoski, M. Reinikainen, et al. (2000)
• 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)

Browse more research in Mutation Research, or return to medical research.