Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study

Our plain-English summary of Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study, by I. Dianzani, L. Gibello, A. Biava, et al (Mutation Research, 2006).

The study

• Authors: I. Dianzani, L. Gibello, A. Biava, M. Giordano, M. Bertolotti, M. Betti, D. Ferrante, S. Guarrera, G.P. Betta, D. Mirabelli, G. Matullo, C. Magnani
• Journal: Mutation Research
• Published: 2006;599(1-2):124-34
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Differences in response to carcinogenic agents are due to the allelic variants of the genes that control it. Key genes are those involved in the repair of the DNA damage caused by such agents. This paper describes the results of a case-control epidemiological study designed to determine the genotypes of four of these genes in persons exposed to a single genotoxic factor, i.e. asbestos, who had or had not developed malignant mesothelioma (MM). Our working hypothesis was that an imperfect DNA repair, as revealed by subtle polymorphic variants, could reduce protection against the chronic DNA insult provoked by asbestos and eventually result in mutagenesis and cancer. Seven variants (i.e. XRCC1-R399Q-NCBI SNP, XRCC1-R194W, XRCC3-T241M, XRCC3-IVS6-14, XPD-K751Q, XPD-D312N, OGG1-S326C) were investigated in 81 patients and 110 age and sex-matched controls, all residents at Casale Monferrato, a Piedmontese town highly exposed to asbestos pollution. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). When considered as a categorical variable, XRCC1-399Q showed an increased OR both in heterozygotes (OR=2.08; 95% CI=1.00-4.33) and homozygotes (2.38; 95% CI=0.82-6.94), although individual ORs were not significant. When it was considered as a continuous variable OR was significant (OR=1.68; 95% CI: 1.02-2.75). When genotypes were divided into "non-risk" and "risk" genotypes, i.e. those thought to be associated with increased risk in the light of the functional significance of the variants, XRCC1-399Q (Q homozygotes+Q/R heterozygotes versus R homozygotes) had an OR=2.147 (95% CI: 1.08-4.28), whereas that of XRCC3-241T (T homozygotes+M/T heterozygotes versus M homozygotes) was 4.09 (95% CI: 1.26-13.21) and that of OGG1-326C was increased, though not significantly. None of the haplotypes showed a significantly different frequency between patients and controls. This is the first report of an association between polymorphisms in DNA repair genes and asbestos-associated MM. Our data indicate that genetic factors are involved in MM development.

In plain English

This population-based case-control study asked whether inherited variants in four DNA repair genes (XRCC1, XRCC3, XPD and OGG1) were linked to malignant mesothelioma of the pleura. It was set in Casale Monferrato, Italy, where an asbestos cement factory operated from 1907 to 1985. Blood samples came from 81 patients diagnosed between January 2001 and September 2004 and from 110 local residents matched for age and sex. The main analyses used the 70 patients and 85 controls who had been exposed to asbestos, and seven gene variants were tested. Among exposed subjects, mesothelioma risk rose with each copy of the XRCC1-399Q variant (odds ratio 1.68; 95% CI 1.02–2.75). Carrying at least one copy gave an odds ratio of 2.15 (1.08–4.28). For XRCC3-T241M, carrying at least one T variant gave an odds ratio of 4.09 (1.26–13.21), but these genotypes did not fit the expected population pattern (Hardy–Weinberg equilibrium). OGG1 C/C showed a non-significant increase, and no XRCC1, XRCC3 or XPD haplotype (paired variants) differed significantly. The authors concluded that genetic factors are involved in mesothelioma development. They said the small study needs confirmation.

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: Population-based case-control study (genetic association study)
• Who was studied: 81 patients with malignant pleural mesothelioma diagnosed January 2001 to September 2004 and 110 age- and sex-matched controls, all residents of the Local Health Authority of Casale Monferrato, north-west Italy (out of 108 and 250 eligible). The main analyses covered the 70 patients and 85 controls with asbestos exposure.
• Exposure: Asbestos exposure (occupational, domestic and environmental) linked to a local asbestos cement factory, assessed blindly by an industrial hygienist from questionnaires. Fiber types are not specified. The genetic factors studied were seven variants in the DNA repair genes XRCC1, XRCC3, XPD and OGG1.
• Main results:
  • Among asbestos-exposed subjects, mesothelioma risk increased with the number of XRCC1-399Q alleles: OR 1.68 (95% CI 1.02–2.75).
  • Among asbestos-exposed subjects, ORs for XRCC1 R/Q heterozygotes (2.08; 95% CI 1–4.33) and Q/Q homozygotes (2.38; 95% CI 0.82–6.94) were increased but not statistically significant.
  • Among asbestos-exposed subjects, XRCC1 R/Q plus Q/Q compared with R/R: OR 2.15 (95% CI 1.08–4.28), statistically significant.
  • Among asbestos-exposed subjects, XRCC3 T/T plus M/T compared with M/M: OR 4.09 (95% CI 1.26–13.21).
  • Among asbestos-exposed subjects, OGG1-S326C C/C homozygotes had a non-significant increase in risk (OR 6.40; 95% CI 0.66–61.67). C/C compared with all other genotypes gave a non-significant OR of 7.09 (95% CI 0.74–66.67).
  • The other polymorphisms showed only minimal, non-significant differences from controls.
  • Haplotypes (pairs of variants) were analysed only within XRCC1, XRCC3 and XPD. None of these haplotype frequencies differed significantly between patients and controls.
  • For the XRCC1-399Q finding, the estimated false-positive report probability was 0.150 (15%), assuming a prior probability of 25%.
• The authors' conclusion: The authors concluded that this was the first report of an association between a DNA repair gene polymorphism and asbestos-associated mesothelioma, and that their data indicate genetic factors are involved in mesothelioma development.
• Limitations the authors state:
  • The small number of patients and controls means further studies are needed to confirm the findings.
  • XRCC3-T241M genotypes were not in Hardy–Weinberg equilibrium, so the authors felt that result should be confirmed in a larger series.
  • The false-positive report probability estimate is extremely sensitive to the assumed true odds ratio and prior probabilities.
  • A smaller proportion of controls than cases gave blood samples (44% versus 75%), although the authors judged bias from this unlikely.

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, Carcinogenic, Casale Monferrato, Odds Ratio, confidence interval.

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