Polymorphisms of NRF2 and NRF2 target genes in urinary bladder cancer patients.

PURPOSE: NRF2 transcription factor is involved in modulation of various antioxidant and metabolic genes and, therefore, may modulate anti-carcinogenic potential. Association between polymorphisms of NRF2 and five NRF2-regulated genes and urinary bladder cancer (BC) risk was analyzed. METHODS: The study group included 244 BC patients, while the control group comprised 365 individuals with no evidence of malignancy. Genotyping of GSTM1 (deletion), GSTT1 (deletion), GSTA1 -69C/T (rs3957357), GSTP1 Ile105Val (rs1695), SOD2 Ala16Val (rs4880) and NRF2 -617C/A (rs6721961) in blood genomic DNA was performed by means of real-time PCR assays. The associations between gene polymorphism and BC risk were computed by logistic regression. RESULTS: The frequency of GSTA1, GSTP1, SOD2 and NRF2 genotypes did not differ in both groups. A significantly higher BC risk was associated with GSTM1 null genotype after adjusting to age, sex and smoking habit (OR 1.85, 95 % CI 1.30-2.62; P = 0.001). GSTT1 null (OR 0.50, 95 % CI 0.31-0.81; P = 0.005) and GSTP1 Val105Val (OR 0.52, 95 % CI 0.27-0.98; P = 0.04) genotypes were associated with reduced BC risk separately or in combination (OR 0.24, 95 % CI 0.11-0.51; P < 0.0001) (P heterogeneity = 0.01). Combined GSTT1 null and SOD2 with at least one 16Val allele among never smokers encompass reduced BC risk (OR 0.14, 95 % CI 0.03-0.63; P = 0.01) (P heterogeneity = 0.04). CONCLUSIONS: This study supports hypothesis that GSTM1 null genotype may be a moderate BC risk factor. The gene-gene and gene-environment interactions associated with combined GSTP1/GSTT1 and combined GSTT1/SOD2 genetic polymorphisms along with cigarette smoking habit may play a significant role in BC risk modulation.

MMP7 and MMP8 genetic polymorphisms in bladder cancer patients.

INTRODUCTION: Breakdown of the extracellular matrix by matrix metalloproteinases (MMPs), as we know, is one of mechanisms involved and required in tumor invasion. MMP7 is a negative prognostic factor of various malignances, while MMP8 exhibits an inhibitory effect on tumorigenesis and metastasis. We evaluated the potential association of functional polymorphisms in the promoter of the MMP7 (rs11568818) and MMP8 (rs11225395) genes and bladder cancer (BCa) risk. MATERIALS AND METHODS: The study included 241 BCa cases and 199 healthy population controls that were collected at the First Department of Urology, Medical University (Lódz, Poland) and at the Nofer Institute of Occupational Medicine (Lódz, Poland). Genomic DNA samples were isolated from venous blood and genetic polymorphisms were analyzed by real-time polymerase chain reaction using TaqMan fluorescent probes. Associations between genotype and allele status were estimated by logistic regression models adjusted for classic risk factors (e.g. age, gender and cigarette smoking). RESULTS: MMP7 and MMP8 genotypes were distributed similarly in BCa patients and in controls and at least one variant allele was not associated with BCa cancer risk (OR, 0.91; 95% CI, 0.60-1.39; p = 0.662 for MMP7 and OR, 0.96; 95% CI, 0.63-1.46; p = 0.836 for MMP8). We observed higher prevalence of MMP7 GG genotypes among BCa patients than in controls (OR, 1.54; 95% CI, 0.93-2.55; p = 0.093). Additionally, genetic polymorphisms in the MMP7 and MMP8 were not associated with the tumor grade or stage. CONCLUSIONS: Our results suggest that genetic variations in two genes encoding members of the MMP7 and MMP8 are not associated with a risk of BCa in the Caucasian population.

Genetic polymorphisms in matrix metalloproteinases (MMPs) and tissue inhibitors of MPs (TIMPs), and bladder cancer susceptibility.

OBJECTIVES: To elucidate genetic polymorphisms of the matrix metalloproteinases (MMPs) MMP1 (rs1799750), MMP2 (rs243865), MMP9 (rs3918242), MMP12 (rs2276109) and tissue inhibitors of MMPs (TIMPs) TIMP1 (rs2070584) and TIMP3 (rs9619311) genes that may be involved in susceptibility to bladder cancer (BC). PATIENTS AND METHODS: We enrolled 241 patients with BC and 199 controls. Genomic DNA samples were extracted from peripheral blood and polymorphisms were analysed by high-resolution melting analysis and by real-time polymerase chain reaction using TaqMan fluorescent probes. RESULTS: Of the six evaluated polymorphisms of MMPs and TIMPs, only one was found to be associated with BC risk. There was a significant difference for MMP1 (rs1799750) 2G/1G+1G/1G genotype (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.39-0.98; P = 0.042). Additionally, there was a joint effect of this genotype on BC risk among 'ever smokers' (OR 0.51, 95% CI 0.28-0.89; P = 0.019), but not in 'never smokers'. The combined genotype MMP2 -1306C/T (rs243865) allele T with MMP9 -1562C/T (rs3918242) allele T was found to increase BC risk (OR 2.00, 95% CI 1.10-3.62; P = 0.022). CONCLUSIONS: Our results suggest that genetic variations in five polymorphisms of MMPs and TIMPs are not associated with a high risk of BC. Only MMP1 polymorphism may be related to the risk of BC, notably in 'ever smokers'. Our study suggests that the effects of polymorphisms of MMPs and TIMPs on BC risk deserve further investigation.