XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a case-control study

Our plain-English summary of XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a case-control study, by M. Betti, D. Ferrante, M. Padoan, et al (Mutation Research, 2011).

The study

• Authors: M. Betti, D. Ferrante, M. Padoan, S. Guarrera, M. Giordano, A. Aspesi, D. Mirabelli, C. Casadio, F. Ardissone, E. Ruffini, P.G. Betta, R. Libener, R. Guaschino, G. Matullo, E. Piccolini, C. Magnani, I. Dianzani
• Journal: Mutation Research
• Published: 2011;708(1-2):11-20
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare aggressive tumor associated with asbestos exposure. The possible role of genetic factors has also been suggested and MPM has been associated with single nucleotide polymorphisms (SNPs) of xenobiotic and oxidative metabolism enzymes. We have identified an association of the DNA repair gene XRCC1 with MPM in the population of Casale Monferrato, a town exposed to high asbestos pollution. To extend this observation we examined 35 SNPs in 15 genes that could be involved in MPM carcinogenicity in 220 MPM patients and 296 controls from two case-control studies conducted in Casale (151 patients, 252 controls) and Turin (69 patients, 44 controls), respectively. Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Two DNA repair genes were associated with MPM, i.e. XRCC1 and ERCC1. Considering asbestos-exposed only, the risk increased with the increasing number of XRCC1-399Q alleles (Casale: OR=1.44, 95%CI 1.02-2.03; Casale+Turin: OR=1.34, 95%CI 0.98-1.84) or XRCC1 -77T alleles (Casale+Turin: OR=1.33, 95%CI 0.97-1.81). The XRCC1-TGGGGGAACAGA haplotype was significantly associated with MPM (Casale: OR=1.76, 95%CI 1.04-2.96). Patients heterozygotes for ERCC1 N118N showed an increased OR in all subjects (OR=1.66, 95%CI 1.06-2.60) and in asbestos-exposed only (OR=1.59, 95%CI 1.01-2.50). When the dominant model was considered (i.e. ERCC1 heterozygotes CT plus homozygotes CC versus homozygotes TT) the risk was statistically significant both in all subjects (OR=1.61, 95%CI 1.06-2.47) and in asbestos-exposed only (OR=1.56, 95%CI 1.02-2.40). The combination of ERCC1 N118N and XRCC1 R399Q was statistically significant (Casale: OR=2.02, 95%CI 1.01-4.05; Casale+Turin: OR=2.39, 95%CI 1.29-4.43). The association of MPM with DNA repair genes support the hypothesis that an increased susceptibility to DNA damage may favour asbestos carcinogenicity.

Copyright © 2011 Elsevier B.V. All rights reserved.

In plain English

This Italian case-control study asked whether DNA variants in repair, redox and inflammation genes were associated with malignant pleural mesothelioma (MPM). The authors tested 35 variants in 15 genes using blood from two studies. One was population-based in Casale Monferrato, exposed through an asbestos cement factory (151 patients, 252 controls). The other was hospital-based, in Turin (69 patients, 44 controls). In the case-control analysis, only XRCC1 and ERCC1, both DNA repair genes, were significantly associated with MPM; a meta-analysis with an earlier study also linked APEX. Among asbestos-exposed people in Casale, the odds of MPM rose with each XRCC1-399Q copy (OR 1.44, 95% CI 1.02 to 2.03). Adding Turin, this became borderline (OR 1.34, 0.98 to 1.84). Pooling both panels, one ERCC1 N118N copy was associated with MPM (OR 1.66, 1.06 to 2.60). Pooled exposed people with at least one variant copy of both XRCC1 R399Q and ERCC1 N118N had an OR of 2.39 (1.29 to 4.43) versus people carrying neither. The authors noted a low response rate. They stressed that these genetic risks (OR 1 to 2) were far below the risk from asbestos (OR 50 to 100).

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: Genetic association analysis in two case-control studies: a population-based study in Casale Monferrato and a hospital-based study in Turin, Italy; plus a meta-analysis with one earlier study and a gene-expression analysis in normal pleural tissue
• Who was studied: Casale Monferrato: 151 MPM patients recruited January 2001 to December 2006 and 252 population controls. Turin area: 69 MPM patients admitted January 2004 to October 2008 and 44 hospital controls. After excluding patients with undefined asbestos exposure, the analyses covered 201 patients and 296 controls pooled. All participants were Caucasian.
• Exposure: 35 single nucleotide polymorphisms in 15 genes (DNA repair, redox state control, inflammation) studied together with asbestos exposure. Exposure was assessed blindly by an industrial hygienist as occupational, household, environmental or none. In Casale, exposure came largely from an asbestos cement factory active 1907 to 1986. Fiber types are not specified.
• Main results:
  • In the case-control analysis, of the 15 genes only two, XRCC1 and ERCC1, both involved in DNA repair, were significantly associated with MPM.
  • Casale Monferrato, asbestos-exposed only: the risk of MPM increased with the number of XRCC1-399Q alleles (OR = 1.44, 95%CI 1.02–2.03).
  • Casale and Turin pooled, asbestos-exposed only: the XRCC1-399Q association was borderline significant (OR = 1.34, 95%CI 0.98–1.84).
  • Excluding the subjects from the authors' previous paper, the XRCC1-399Q OR in asbestos-exposed individuals was 1.25 (95%CI 0.76–2.06), based on 55 patients and 109 controls.
  • Pooled panels: ERCC1 N118N heterozygotes, compared with wild-type, had OR = 1.66 (95%CI 1.06–2.60) in all subjects and OR = 1.59 (95%CI 1.01–2.50) in asbestos-exposed only. Homozygotes CC showed no association, which the authors attributed probably to the small size of that group.
  • ERCC1 dominant model (CT plus CC versus TT): OR = 1.61 (95%CI 1.06–2.47) in all subjects and OR = 1.56 (95%CI 1.02–2.40) in asbestos-exposed only.
  • Asbestos-exposed subjects with at least one variant allele for both ERCC1 N118N and XRCC1 R399Q, compared with the reference group of ERCC1 TT and XRCC1 GG genotypes (no variant allele at either): OR = 2.02 (95%CI 1.01–4.05) in Casale and OR = 2.39 (95%CI 1.29–4.43) in Casale and Turin pooled.
  • Among asbestos-exposed subjects in Casale (131 cases, 194 controls), the XRCC1-TGGGGGAACAGA haplotype was associated with increased MPM risk (OR = 1.76, 95%CI 1.04–2.96). No ERCC1 haplotype was significantly associated.
  • Pooled asbestos-exposed subjects: XRCC1 −77CC homozygotes gave some indication of a protective effect (OR = 0.52, 95%CI 0.27–1.01), but this was not statistically significant.
  • In a meta-analysis with Gemignani et al. (252 patients, 356 controls, asbestos exposure not considered), APEX EE homozygotes had OR = 1.72 (95%CI 1.02–2.91) and ERCC1 118N heterozygotes had OR = 1.51 (95%CI 1–2.26). XRCC1 R399Q was not associated with MPM. The authors said more data are needed to ascertain the APEX association.
  • In 71 normal pleural tissue samples, XRCC1 expression did not differ significantly between XRCC1 −77T>C genotypes (p = 0.3).
  • The authors stated that the genetic risks were one to two orders of magnitude lower than the risk from asbestos exposure itself.
• The authors' conclusion: The authors concluded that the study shows an association between two DNA repair genes and MPM and strengthens the hypothesis that genetic risk factors play a role in asbestos carcinogenicity.
• Limitations the authors state:
  • Low response rate and selection of patients
  • The Turin panel alone never reached statistical significance, probably because of its small size
  • Turin study was still under way, so suitable controls had not yet been included for part of the patients
  • Asbestos exposure could not be taken into account in the meta-analysis
  • Gene expression was measured in whole pleural tissue, not specifically in mesothelial cells

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, Case-Control Study, Pleural Mesothelioma, Asbestos Exposure, Casale Monferrato, Odds Ratio, confidence interval.

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• Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival — Z.G. Zimling, J.B. Sørensen, et al. (2012)
• ¹⁸F-FDG uptake on PET could be a predictive marker of excision repair cross-complementation group 1 (ERCC1) expression in patients with thoracic neoplasms? — K. Kaira, M. Endo, et al. (2012)
• Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients — T. Powrózek, D.M. Kowalski, et al. (2014)

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