Polymorphisms in oxidative stress-related genes and mortality in breast cancer patients--potential differential effects by radiotherapy?

Abstract

We assessed whether variants in 22 oxidative stress-related genes are associated with mortality of breast cancer patients and whether the associations differ according to radiotherapy. Using a prospective cohort of 1348 postmenopausal breast cancer patients, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for 109 single nucleotide polymorphisms (SNPs) using Cox proportional hazards regression. Validation of results was attempted using two Scandinavian studies. Eleven SNPs in MT2A, NFE2L2, NQO1, PRDX1, and PRDX6 were significantly associated with overall mortality after a median follow-up of 5.7 years. Three SNPs in NQO1 (rs2917667) and in PRDX6 (rs7314, rs4916362) were consistently associated with increased risk of dying across all three study populations (pooled: HRNQO1_rs2917667 1.20, 95% CI 1.00-1.44, p = 0.051; HRPRDX6_rs7314 1.16, 95% CI 1.00-1.35, p = 0.056, HRPRDX6_rs4916362 1.14 95% CI 1.00-1.32, p = 0.062). Potential effect modification by radiotherapy was found for CAT_rs769218. In conclusion, genetic variants in NQO1 and PRDX6 may modify breast cancer prognosis.

Keywords: BCSS; Breast cancer prognosis; CAT; CI; CTx; CYBA; ER; Effect modification; GPX1; GSR; GSTA1; GSTO1; Genetic variants; HMOX1; HR; HSPB1; HWE; Hardy–Weinberg equilibrium; LD; MAF; MPO; MT2A; MnSOD; NAD(P)H; NAD(P)H dehydrogenase quinone 1; NFE2L2; NOS3; NQO1; OS; Oxidative stress; PR; PRDX; RTx; Radiotherapy; SNP; SOD1; SOD2; TNF; TXN; TXN2; TXNRD1; TXNRD2; breast cancer-specific survival; catalase; chemotherapy; confidence interval; cytochrome b-245 alpha polypeptide; glutathione S-transferase alpha 1; glutathione S-transferase omega; glutathione peroxidase 1; glutathione reductase; hazard ratio; heat shock 27 kDa protein 1; heme oxygenase 1; linkage disequilibrium; manganase superoxide dismutase, see also SOD2; metallothionein 2A; minor allele frequency; myeloperoxidase; nicotinamide adenine dinucleotide phosphate; nitric oxide synthase 3, endothelial nitric oxide synthase; nuclear factor erythroid-derived 2-like 2; oestrogen receptor; overall survival; peroxiredoxin; progesterone receptor; radiotherapy; single nucleotide polymorphism; superoxide dismutase 1; superoxide dismutase 2, mitochondrial, see also MnSOD; thioredoxin 2, mitochondrial; thioredoxin reductase 1, cytosolic; thioredoxin reductase 2, mitochondrial; thioredoxin, cytosolic; tumor necrosis factor.