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][2][3][4][5][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][9][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][2][3][4][5][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 refer...

Genetic polymorphisms in Glutathione S-transferase Omega (GSTO) and cancer risk: a meta-analysis of 20 studies

“…In total, 20 articles 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 were identified according to the inclusion and exclusion criteria. The flow chart of literature search and study selection was illuminated in Figure 1 .…”

“…Among the 20 articles, 5 of them were studies of Caucasian 9 12 15 19 27 , 10 studies were of Asian 10 11 17 18 20 24 25 26 28 29 and the rest were study of different races (white and non-white groups) 13 16 21 22 23 . Cancer cases were all diagnosed histologically or pathologically in these studies.…”

Haplotype analysis of XRCC1 (at codons 194 and 399) and susceptibility to breast cancer, a meta-analysis of the literatures

“…There was no study examined the gene-gene and geneenvironment interactions, and so on. Finally, very recently it is reported that polymorphisms of two penetrance genes of XRCC1, and xenobiotic metabolizing enzymes have additive effect on susceptibility to breast cancer [52]. Not only for breast cancer risk, but also for other multifactorial diseases polymorphisms of low penetrance genes have additive effect on development of gastric and colorectal cancers [53][54][55] and asthma [56].…”

Susceptibility to Breast Cancer and Three Polymorphisms of GSTZ1

“…Previously we reported that the combination of members of GST classes are associated with increased risk of colorectal, gastric, and breast cancers (Saadat and Saadat, 2001;Marahatta et al, 2006;Masoudi et al, 2009Masoudi et al, , 2010Mo et al, 2009;Zhuo et al, 2009). Induction of GST subunits was deleted in the liver of Gstz1 -/ -mice.…”

“…The association between polymorphisms of several classes of GSTs (such as members of GSTy and GSTm) and several types of cancers has been extensively studied (Saadat and Saadat, 2001;Marahatta et al, 2006;Saadat, 2006;Masoudi et al, 2009Masoudi et al, , 2010Mo et al, 2009;Zhuo et al, 2009). However, there is no so much data on association between GSTz and susceptibility to cancers (Smith et al, 2001;Andonova et al, 2009).…”