Additive effects of genetic variations of xenobiotic detoxification enzymes and DNA repair gene XRCC1 on the susceptibility to breast cancer

Abstract

Association between polymorphisms of X-ray repair crosscomplementation group 1 (XRCC1, at codons 194 and 399) and also several classes of glutathione S-transferases (GSTs such as GSTS1, GSTL1) and risk of breast cancer have been studied extensively [1–6]. A significant association has been found between XRCC1 Arg399Gln polymorphism and breast cancer risk [1, 2]. The null genotype of GSTM1 increased the risk of breast cancer [6]. There is only one study investigating the association between genetic polymorphism of GSTO2 N142D and risk of breast cancer, using very small sample size. However, no significant association was reported [7]. There is no study investigating the additive effects of these polymorphisms and the breast cancer risk. To get more insight into the possibility of contribution of these genetic variations to susceptibility of breast cancer, the present study was done. The present case–control study used participants from our previous study [8]. We lost DNA samples of 11 subjects. Therefore, we include 181 breast cancer patients and 181 healthy subjects in the analysis. Informed consent was obtained from all participants, and the study was approved by the institutional review board at our university. Genotypic analysis for the study polymorphisms and laboratory quality control were described previously [3, 8–10]. Frequency of the GSTM1 null genotype among breast cancer patients and control subjects were 61.3 and 50.2%, respectively. There was significant difference between cases and controls (OR = 1.56, 95% CI: 1.03–2.38, P = 0.035). The prevalence of GSTT1 null genotype was similar between cases and controls (25.9 vs. 24.8%; OR = 1.06, 95% CI: 0.66–1.70, P = 0.809). In the recessive effect of the 399Gln allele of XRCC1 (comparison between Gln/Gln versus Arg/Arg ? Arg/Gln), Gln/Gln genotype significantly increased the risk of breast cancer (OR = 2.21, 95% CI: 1.16–4.19, P = 0.015). The association between Arg194Trp polymorphism of XRCC1 and breast cancer risk was not significant (Trp/Trp ? Arg/Trp versus Arg/Arg genotype; OR = 1.36, 95% CI: 0.79–2.37, P = 0.266). The present results confirmed previous reports [1–6]. For the N142D polymorphism of GSTO2, the prevalence of NN, ND, and DD were 44.2, 43.1, and 12.7% in control group and 40.9, 41.4, and 17.7% among patient subjects, respectively. The ND (OR = 1.04, 95% CI: 0.66–1.62, P = 0.865) and DD (OR = 1.50, 95% CI: 0.80–2.80, P = 0.198) genotypes had no significant effect on risk of breast cancer, in comparison with the NN genotype. Neither recessive (OR = 1.47, 95% CI: 0.82–2.63, P = 0.189) nor dominant (OR = 1.15, 95% CI: 0.75–1.75, P = 0.524) models of the 142D allele were significant, confirming previous report [7]. Genetic polymorphisms that were significant by P \ 0.3 (GSTM1, GSTO2, XRCC1 at codons 194 and 399) in the univariate analysis were included in the analysis for investigating the additive effects of the genotypes. Table 1 showed the profiles of GSTs and XRCC1 genotypes in control and cancerous groups. The reference group consisted of individuals having four putative low risk genotypes. Statistical analysis showed that the risk of breast cancer increased as a function of number of putative high risk genotypes (Table 2). This finding suggests that these M. Masoudi I. Saadat M. Saadat (&) Department of Biology, College of Sciences, Shiraz University, 71454 Shiraz, Iran e-mail: saadat@susc.ac.ir; msaadat41@yahoo.com