Oxidative stress in susceptibility to breast cancer: study in Spanish population

Abstract

Background: Alterations in the redox balance are involved in the origin, promotion and progression of cancer. Inter-individual differences in the oxidative stress regulation can explain a part of the variability in cancer susceptibility.The aim of this study was to evaluate if polymorphisms in genes codifying for the different systems involved in oxidative stress levels can have a role in susceptibility to breast cancer.

Methods: We have analyzed 76 single base polymorphisms located in 27 genes involved in oxidative stress regulation by SNPlex technology. First, we have tested all the selected SNPs in 493 breast cancer patients and 683 controls and we have replicated the significant results in a second independent set of samples (430 patients and 803 controls). Gene-gene interactions were performed by the multifactor dimensionality reduction approach.

Results: Six polymorphisms rs1052133 (OGG1), rs406113 and rs974334 (GPX6), rs2284659 (SOD3), rs4135225 (TXN) and rs207454 (XDH) were significant in the global analysis. The gene-gene interactions demonstrated a significant four-variant interaction among rs406113 (GPX6), rs974334 (GPX6), rs105213 (OGG1) and rs2284659 (SOD3) (p-value = 0.0008) with high-risk genotype combination showing increased risk for breast cancer (OR = 1.75 [95% CI; 1.26-2.44]).

Conclusions: The results of this study indicate that different genotypes in genes of the oxidant/antioxidant pathway could affect the susceptibility to breast cancer. Furthermore, our study highlighted the importance of the analysis of the epistatic interactions to define with more accuracy the influence of genetic variants in susceptibility to breast cancer.

Figure 1

The polymorphisms rs406113, rs974334, rs1052133 and rs2284659, showing the highest statistical significance in the combinatorial set 1  +  set 2, were chosen for the gene-gene interaction analysis. The MDR analysis was done with the genotypes collapsed according to the genetic models selected: rs1052133 (OGG1) recessive model; CC/CG vs.GG, rs406113 (GPX6) dominant model; CC/AC vs. AA, rs974334 (GPX6) recessive model; CC/CG vs. GG, rs2284659 (SOD3) recessive model; GG/GT vs. TT. The figure shows the summary of four-loci genotype combinations associated with high and low risk. Cases: left bars, controls: right bars. The epistatic gene-gene interaction corresponds to the high risk combinations (darkest color).