Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Abstract

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. [Cancer Res 2009;69(17):6857-64]

Genetic Variants of NBS1 Predict Clinical Outcome of Platinum-based Chemotherapy in Advanced Non-small Cell Lung Cancer in Chinese

“…Publications on NBS1 polymorphisms have mainly focused on rs1805794 and the risk of cancers including lung, breast, bladder, renal cell cancers, non-Hodgkin lymphoma and childhood acute leukemia (Medina et al, 2003;Lan et al, 2005;Zienolddiny, 2005;Landi et al, 2006;Ryk et al, 2006;Hsu et al, 2007;Choudhury et al, 2008;Margulis et al, 2008;Mosor et al, 2008;Schuetz et al, 2009;Stern et al, 2009;Park et al, 2010), but the results were not consistent. A recent meta-analysis on rs1805794 has shed light on a positive association between the variant genotype of rs1805794 and the risk of multiple cancers (MeiXia et al, 2009).…”

“…Rs1805794 located in exon 5 of NBS1 is one of the most common polymorphisms and can induce an amino acid substitution from Glu to Gln. Studies have investigated the association between rs1805794 and risk of multiple cancers, such as lung, breast, bladder and nasopharyngeal carcinoma (Medina et al, 2003;Lan et al, 2005;Lu et al, 2006;Hsu et al, 2007;Stern et al, 2009;Zheng et al, 2011). However, only one study has explored the effect of this polymorphism on prognosis of human cancer and reported that it was not associated with the survival of esophagus or gastric adenocarcinoma after platinum-based neoadjuvant poly-chemotherapy (Ott et al, 2011).…”

Common genetic variants in the PSCA gene influence gene expression and bladder cancer risk

“…Traditional candidate gene association studies focused on genes involved in detoxification of environmental carcinogens and DNA repair pathways (9)(10)(11)(12). Recently, genome-wide association studies (GWAS) have advanced our knowledge of the genetic architecture of bladder cancer by discovering a number of new bladder cancer-associated loci (13)(14)(15)(16)(17).…”

937 Attenuated XPC expression is not associated with impaired DNA repair in bladder cancer

“…Several lines of evidence suggest that NER genes play a role in the development and progression of BC; polymorphisms in some NER genes increase BC risk, especially in smokers [9][10][11][12]. Furthermore, it was shown that attenuated expression of the NER protein XPC is present iñ 40% of all bladder tumors and a contributing factor in tumor progression [13].…”