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

Mutation Research. 2006 Mar 23; [Epub ahead of print] [Link]

I. Dianzania, b, L. Gibelloa, A. Biavaa, M. Giordanoc, M. Bertolottid, M. Bettia, D. Ferranted, S. Guarrerae, G.P. Bettaf, D. Mirabellib, d, G. Matulloe and C. Magnanib, d

aLaboratorio di Patologia Genetica, Dipartimento di Scienze Mediche, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
bInterdepartmental Center “G. Scansetti” of the University of Torino for Studies on Asbestos and other Toxic Particulates, Torino, Italy
cLaboratorio di Genetica, Dipartimento di Scienze Mediche, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
dCPO-Piemonte and Unità di Statistica Medica ed Epidemiologia, Dipartimento di Scienze Mediche, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
eDipartimento di Genetica, Biologia e Biochimica, Università di Torino, Via Santena 19, 10126 Torino, Italy
fOspedale S. Maurizio e Lazzaro, Dip. Oncologia, Unita’ di Anatomia Patologica, Alessandria, Italy

Received 19 September 2005;  revised 23 January 2006;  accepted 15 February 2006.  Available online 27 March 2006.


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.

Keywords: Genetic polymorphisms; DNA repair genes; Asbestos; Malignant mesothelioma