Comprehensive analyses of DNA repair pathways, smoking and bladder cancer risk in Los Angeles and Shanghai

Abstract

Tobacco smoking is a bladder cancer risk factor and a source of carcinogens that induce DNA damage to urothelial cells. Using data and samples from 988 cases and 1,004 controls enrolled in the Los Angeles County Bladder Cancer Study and the Shanghai Bladder Cancer Study we investigated associations between bladder cancer risk and 632 tagSNPs that comprehensively capture genetic variation in 28 DNA repair genes from four DNA repair pathways: base excision repai, nucleotide excision repair (NER), non-homologous end-joining (NHEJ), and homologous recombination repair (HHR). Odds ratios (ORs) and 95% confidence intervals (CIs) for each tagSNP were corrected for multiple testing for all SNPs within each gene using pACT, and for genes within each pathway and across pathways with Bonferroni. Gene and pathway summary estimates were obtained using ARTP. We observed an association between bladder cancer and POLB rs7832529 (BER) (pACT = 0.003; ppathway = 0.021) among all, and SNPs in XPC (NER) and OGG1 (BER) among Chinese men and women, respectively. The NER pathway showed an overall association with risk among Chinese males (ARTP NER p = 0.034). The XRCC6 SNP rs2284082 (NHEJ), also in LD with SREBF2, showed an interaction with smoking (Smoking status interaction pgene = 0.001, ppathway = 0.008, poverall = 0.034). Our findings support a role in bladder carcinogenesis for regions that map close to or within BER (POLB, OGG1) and NER genes (XPC). A SNP that tags both the XRCC6 and SREBF2 genes strongly modifies the association between bladder cancer risk and smoking.

EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016

“…The value of FC for improvement of outcome in relation to progression rate and survival remains to be demonstrated. 6.7.5.2. Narrow-band imaging.…”

Effects of the Ser326Cys Polymorphism in the DNA Repair OGG1 Gene on Cancer, Cardiovascular, and All-Cause Mortality in the PREDIMED Study: Modulation by Diet

“…However, a strong association was detected between the Cys326Cys risk genotype and cardiovascular mortality. Although in comparison to studies that have examined the possible association between the OGG1-rs1052133 polymorphism and cancer [18][19][20][21][22][23][24][25][26][27][28][29][30][31] , very few have examined its association with cardiovascular disease [33][34][35]54 , studies in animal models on OGG1 function strongly support this association 32,59,60 . Thus, in a study by Tumurkhuu et al 32 in Ogg1(-/-) mice, the authors observed a more atherogenic profile of the different markers analyzed in comparison with mice with a normal Ogg1 gene expression.…”

“…This observation agrees with several functional studies showing that only homozygous carriers of the Cys allele showed a significantly lower DNA repair activity compared to Ser326Ser 16,18 . A potential source of the observed heterogeneity found among studies may be the exposure to different environmental factors [28][29][30][31] (i.e. mainly vegetable intake and other dietary factors).…”

Modeling the Complex Exposure History of Smoking in Predicting Bladder Cancer

“…It has not been measured whether rapid acetylators are more likely to be high intensity/short duration smokers. Moreover, there is heterogeneity in the efficiency of DNA repair pathways between individuals; for example, those who have a slow N-acetyltransferase phenotype have a higher risk of UBC when they smoke (40), and DNA repair processes can also be negatively influenced by longer smoking duration or higher cumulative exposure (in pack-years) (41). This indicates that the DNA adduct pathway of UBC pathogenesis is important in smoking-related UBC.…”