Abstract A97: Dietary nitrosamines, genetic variation in DNA repair and metabolism genes, and bladder cancer risk in the Los Angeles Bladder Cancer Study

Abstract

Abstract Background: N-nitroso compounds (NOCs) can cause direct DNA damage and are known to induce a wide range of tumors, including tumors of the bladder in animal models. Humans are exogenously exposed to NOCs via diet, in particular processed meats, and cigarette smoke. However, NOCs, such as the carcinogen N-nitrosodimethylamine (NDMA), can also be formed endogenously from their dietary precursors: nitrates, nitrites and amines. The heme found in red meat is a potent stimulator of this endogenous formation. Our previous findings from the Los Angeles Bladder Cancer Study show that intake of meats with concurrent high amine and heme content, such as salami and liver, are associated with an increased risk of bladder cancer. Once NOCs are formed, they need to be activated metabolically by cytochrome P450 enzymes into electrophilic intermediates to exert a carcinogenic effect. These intermediates then react with DNA to form bulky adducts which, if not repaired, can lead to DNA instability and ultimately DNA damage. These reactive intermediates can also undergo metabolism by glutathione S-transferases (GSTs), which results in their detoxification. Multiple DNA repair pathways are available to correct NOC-induced damage. Methods: We examined the role of dietary sources of NOCs and NOC precursors in conjunction with variation in genes involved in NOC metabolism and DNA repair in the risk of bladder cancer using 355 bladder cancer cases and 409 controls from the Los Angeles Bladder Cancer Study, a population-based case-control study. We tested each of 627 SNPs in 27 genes involved in NOC metabolism and DNA repair for effect modification of exposure to different dietary sources of NOCs and NOC precursors. Multiple testing was accounted for using a global Bonferroni correction, across all SNPs combined, and also at the gene and pathway levels. Results: A polymorphism in the base excision repair gene hOGG1 (Ser326Cys; rs1052133) was shown to modify the effect of intake of high amine and heme content meats with a globally corrected p-value of 0.014 (crude p-value = 3.7 x 10-5). We found that the previously identified positive association between intake of high amine and heme content meat intake and bladder risk was restricted to individuals carrying one or more copies of the hOGG1 codon 326 Cys allele, which has been reported to reduce OGG1 protein activity. Conclusion: Results of this study build upon our previous findings that consumption of meats with high amine and heme content, such as salami and liver, are potential risk factors for bladder cancer. Our current finding of modification of this association by a DNA repair variant supports a role for endogenous dietary nitrosamines in bladder carcinogenesis. Citation Format: Chelsea E. Catsburg, Roman Corral, Juan Pablo Lewinger, Amit D. Joshi, Manuela Gago-Dominguez, Jian-Min Yuan, Victoria K. Cortessis, Malcolm C. Pike, Mariana C. Stern. Dietary nitrosamines, genetic variation in DNA repair and metabolism genes, and bladder cancer risk in the Los Angeles Bladder Cancer Study. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A97.