Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism

Our plain-English summary of Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism, by F. Gemignani, M. Neri, F. Bottari, et al (Mutation Research, 2009).

The study

• Authors: F. Gemignani, M. Neri, F. Bottari, R. Barale, P.A. Canessa, F. Canzian, M. Ceppi, I. Spitaleri, M. Cipollini, G.P. Ivaldi, M. Mencoboni, P. Scaruffi, G.P. Tonini, D. Ugolini, L. Mutti, S. Bonassi, S. Landi
• Journal: Mutation Research
• Published: 2009;671(1-2):76-83
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mostly attributable to asbestos exposure. Many polymorphic genes encoding for xenobiotic and oxidative metabolism enzymes (XME) or involved in genome stability (GS) can modulate individual MPM risk in exposed populations. An association study was carried out in a case-control setting including 119 MPM patients and two groups of referent subjects (104 with and 695 without documented asbestos exposure). Forty-eight polymorphisms in XME genes and 75 in GS-genes were evaluated. Statistical analysis revealed some significant associations of studied polymorphisms with MPM risk, but most of them disappeared after applying Bonferroni correction (new threshold for statistical significance: p=4.07 x 10(-4)). On the other hand, the nucleotidic change 282C>T within NAT2 held the statistical significance (OR=3.54; 95% CI 1.75-7.16; p=0.0002), reinforcing existing evidences that describe genetic polymorphisms of NAT2 possibly involved in the etiology of the MPM.

In plain English

This Northern Italian case-control study asked whether inherited gene variants were associated with malignant pleural mesothelioma. Between 1999 and 2006, 119 patients were recruited at three hospitals in asbestos-related industrial and shipping areas. They were compared with 104 controls whose asbestos history was recorded and 695 extra blood donors whose history could not be defined. The authors tested 48 variants in genes that process foreign substances and 75 in DNA-maintenance genes. Several associations appeared, but the authors reported that only the NAT2 variant 282C > T survived correction for multiple testing. People with two copies had an odds ratio of 3.54 (95% CI 1.75–7.16) versus those with two common copies, using pooled controls. Against the 104 recorded-history controls alone it was 1.59 (0.61–4.16). Their table, however, also shows p = 0.0003, below that threshold, for two copies of NAT1 T153T, a variant they said had too few cases. The authors concluded that the effect of variants in these genes is very low, if any. They noted few patients and that only the first control group had asbestos exposure assessed.

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 genetic association study
• Who was studied: 119 malignant pleural mesothelioma patients recruited consecutively from 1999 to 2006 at three general hospitals in Northern Italy (Genova and La Spezia areas). Controls were 104 people (controls-1: blood donors and hospital patients from the same hospitals and areas) whose asbestos exposure history was recorded by questionnaire, plus 695 extra blood donors (controls-2) for whom asbestos exposure history could not be defined. All were Caucasian.
• Exposure: The factors studied were inherited gene variants: 48 polymorphisms in xenobiotic and oxidative metabolism genes and 75 in genome stability (DNA maintenance) genes. Past asbestos exposure was classified from occupational histories, for cases and controls-1 only, as no/unlikely, intermediate/low, or high (mostly carpenters, shipyard caulkers and dockers). High exposure applied to 85 of 119 cases (71.4%) and 17 of 104 controls-1 (16.3%). No fiber types were named.
• Main results:
  • Before correction for multiple testing, the GSTM1 null genotype had an odds ratio of 1.61 (95% CI 1.03–2.53) against the pooled controls.
  • Before correction, specific genotypes in the NAT1 and NAT2 genes showed increased risks, with odds ratios ranging from 2.64 to 25.04.
  • Before correction, statistically significant associations were also found for specific genotypes in several DNA-maintenance genes.
  • The authors reported that after Bonferroni correction (new significance threshold p = 4.07 × 10−4), only the NAT2 282C > T association remained statistically significant.
  • For NAT2 282C > T, people homozygous for the variant had an odds ratio of 3.54 (95% CI 1.75–7.16, p = 0.0002) compared with people homozygous for the more frequent allele, using the pooled controls.
  • For NAT2 282C > T homozygotes compared with controls-1 alone (the group with recorded asbestos history), the odds ratio was 1.59 (95% CI 0.61–4.16).
  • Table 2 also reports, for people homozygous for NAT1 T153T, an odds ratio of 10.05 (95% CI 2.19–46.23) with p = 0.0003 against the pooled controls. That p-value is below the stated Bonferroni threshold, although the text says only NAT2 282C > T remained significant. The authors listed NAT1 T153T among the polymorphisms with too few cases in the risk category for solid statistics.
  • When the authors tested, using controls-1 only, whether asbestos exposure modified the effect of any polymorphism, no association was statistically significant after adjustment for multiple comparisons.
• The authors' conclusion: The authors concluded that the effect of polymorphisms in these genes on mesothelioma risk is very low, if any. They regarded the NAT2 association as relevant.
• Limitations the authors state:
  • The number of cases could not be increased, which limited the statistics. For several polymorphisms, including NAT1 T153T, there were too few cases in the risk category.
  • The authors said the associations other than NAT2 282C > T should be considered with extreme caution and are highly likely to be random findings.
  • Asbestos exposure was assessed only for controls-1, and most of these controls were unexposed.
  • Asbestos exposure patterns differed between cases and 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: Pleural Mesothelioma, Asbestos Exposure, Statistical Significance, Etiology.

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