Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma

Our plain-English summary of Polymorphisms of glutathione-S-transferase M1 and manganese superoxide dismutase are associated with the risk of malignant pleural mesothelioma, by S. Landi, F. Gemignani, M. Neri, et al (International Journal of Cancer, 2007).

The study

• Authors: S. Landi, F. Gemignani, M. Neri, R. Barale, S. Bonassi, F. Bottari, P.A. Canessa, F. Canzian, M. Ceppi, R. Filiberti, G.P. Ivaldi, M. Mencoboni, P. Scaruffi, G.P. Tonini, L. Mutti, R. Puntoni
• Journal: International Journal of Cancer
• Published: 2007;120(12):2739-43
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Individual response to oxidative stress, due to exposure to asbestos fibres plays a significant role in the malignant pleural mesothelioma (MPM) etiology. The differential impact on MPM risk of polymorphic alleles of glutathione-S-transferases (GSTs) and manganese superoxide dismutase (MnSOD/SOD2) genes involved in the defence against oxidative damage has been investigated. Ninety cases of MPM and 395 controls were genotyped using the arrayed-primer extension technique. Logistic regression analysis was applied to assess the predictive role of single nucleotide polymorphisms (SNPs) potentially involved in MPM carcinogenesis after adjustment for potential confounders. An increased risk of MPM was found in subjects bearing a GSTM1 null allele (OR = 1.69, 95% CI = 1.04-2.74; p = 0.034), and in those with the Ala/Ala genotypes at codon 16 within MnSOD (OR = 3.07, 95% CI = 1.55-6.05; p = 0.001). A stronger effect of MnSOD was observed among patients without a clear exposure to asbestos fibres. No effect was found for GSTA2, GSTA4, GSTM3, GSTP1 and GSTT1 genes. These findings, if replicated, contribute substantial evidence to the hypothesis that oxidative stress and cellular antireactive oxygen species systems are involved in the pathogenesis and in the natural history of MPM.

In plain English

This Italian case-control study asked whether inherited variations in antioxidant enzyme genes were linked to malignant pleural mesothelioma (MPM). The authors tested DNA from 90 people with MPM, diagnosed between 1996 and 2003 at three Northern Italy hospitals (Genova, Casale Monferrato and La Spezia). They compared them with 395 controls: blood donors and hospital patients without cancer or respiratory disease. Results were adjusted for sex and age. People lacking a working GSTM1 gene (the "null" form) had higher odds of MPM (odds ratio 1.69, 95% CI 1.04–2.74). People carrying two copies of the Ala form of the MnSOD (SOD2) gene at codon 16 also had higher odds than those with two Val copies (odds ratio 3.07, 95% CI 1.55–6.05). No clear effect was found for GSTA2, GSTA4, GSTM3, GSTP1 or GSTT1. Among cases with no evidence of asbestos exposure or low exposure, the odds ratio for the two-Ala MnSOD genotype was 10.72 (95% CI 1.33–86.68), with n = 9. This was not significantly different from the overall figure. The authors concluded that MnSOD variants may play a role in MPM and that further studies are warranted.

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: Hospital-based case-control study of genetic polymorphisms (genotyping with logistic regression adjusted for gender and age)
• Who was studied: 90 MPM cases diagnosed March 1996 to August 2003 at 3 general hospitals in Northern Italy (Genova, Casale Monferrato, La Spezia), and 395 controls drawn from blood donors and from patients hospitalized for nonneoplastic, nonrespiratory conditions. 82.2% of cases and 54.9% of controls were men.
• Exposure: The main factors studied were genetic variants in SOD2 (MnSOD) and in GSTM1, GSTM3, GSTP1, GSTT1, GSTA2 and GSTA4. Asbestos exposure (occupational, residential or other) was recorded for all cases and a sample of controls. Experts classified it blindly as definite high exposure (mostly shipyard and port workers) or 'no evidence/low exposure'. No fiber types are named.
• Main results:
  • The GSTM1 null genotype was associated with MPM: 52 cases and 180 controls were null, versus 37 cases and 199 controls with a functional gene. Odds ratio 1.69, 95% CI 1.04–2.74, p = 0.034.
  • The MnSOD (SOD2) Ala/Ala genotype at codon 16 was associated with MPM: 37 cases and 81 controls, compared with Val/Val (16 cases, 98 controls). Odds ratio 3.07, 95% CI 1.55–6.05, p = 0.001. The Ala/Val genotype showed an odds ratio of 0.99 (95% CI 0.50–1.96).
  • No evident effects were found for the GSTA2, GSTA4, GSTM3, GSTP1 and GSTT1 genes.
  • When cases were split by asbestos exposure, the odds ratio for the GSTM1 null genotype was raised by about the same amount in the high and the low exposure groups. The figures were not shown.
  • For the MnSOD Ala/Ala genotype, the odds ratio was increased in both exposure groups. It was highest in the no evidence/low exposure group (n = 9; OR 10.72, 95% CI 1.33–86.68). The authors noted this was not significantly different from the overall OR. Elsewhere the article reports 15 MPM patients with no or low asbestos exposure in total.
• The authors' conclusion: The authors concluded that the findings add evidence to the hypothesis that MnSOD polymorphisms, likely involving oxidative stress and cellular anti-ROS systems, may play a role in the development of MPM. They said future studies are warranted. The abstract frames the findings as needing replication.
• Limitations the authors state:
  • Because the disease is rare, the study did not reach satisfying statistical power, and subgroups were small.
  • Testing many polymorphisms raises the risk of false positive findings. The authors used the Wacholder method and reported a false positive probability below 20% for the main findings.
  • The low-exposure subgroup result was likely not significantly different from the overall result because few subjects had low asbestos exposure.
  • Some genotyping failed, so not all samples were analyzed for all polymorphisms. For one GSTA4 variant (rs1802061) the success rate could not be raised above 63%.

Topics

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

Medical terms in this study, explained in our Lexicon: Glutathione (GSH), Superoxide, Pleural Mesothelioma, Oxidative Stress, Etiology, Carcinogenesis.

Related studies

• Manganese and extracellular superoxide dismutase polymorphisms and risk for asbestosis — A. Franko, M. Dodic-Fikfak, et al. (2009)
• Asbestos exposure, manganese superoxide dismutase (MnSOD) genotype, and lung cancer risk — L.I. Wang, D. Neuberg, et al. (2004)
• Polymorphism of glutathione S-transferase M1 and lung cancer risk among African-Americans and Caucasians in Los Angeles County, California — S.J. London, A.K. Daly, et al. (1995)
• Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism — F. Gemignani, M. Neri, et al. (2009)
• Vitamin C levels in blood are influenced by polymorphisms in glutathione S-transferases — A. Horska, C. Mislanova, et al. (2011)
• Manganese superoxide dismutase genotypes and asbestos-associated pulmonary disorders — A. Hirvonen, J. Tuimala, et al. (2002)

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