American Association for Cancer Research, Cancer Research, 8_Supplement(72), p. 2646-2646, 2012
DOI: 10.1158/1538-7445.am2012-2646
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Abstract Background: Polycyclic aromatic hydrocarbons (PAHs) play a role in esophageal squamous cell carcinoma in high risk areas where even non-smokers are highly exposed to these compounds. Their early biological effect is the formation of DNA adducts, mediated by phase 1 and 2 pathways and nucleotide excision repair (NER). We aimed at finding a genetic model to explain inter-individual variations in PAH-DNA adduct level among people with similar exposures. Methods: In 111 randomly-selected female non-smokers from the Golestan Cohort Study in Iran, 21 SNPs in 14 genes related to xenobiotic metabolism and 13 SNPs in 9 DNA repair genes were studied (Table). NER capacity was evaluated by a comet assay, and DNA adduct level was measured by 32p-postlabelling. Multivariate regression was used to assess the effects of the number of risk alleles, NER capacity, and environmental exposures on the log-transformed PAH-DNA adduct levels. Models were compared by Akaike's information criterion (AIC). Results: Mean PAH-DNA adduct level was 5.76+3.13 per 108 nucleotides (range: 1.71 - 18.57). The level of PAH-DNA adducts was significantly lower in homozygotes for N-acetyltransferase 2 (NAT2) slow alleles and excision repair cross-complementing (ERCC)-5 T/T genotype, and higher in individuals with myeloperoxidase (MPO) G/G genotype. The sum of risk alleles in these genes had a significant correlation with the log-adduct level (r=0.4, p<0.001). The table shows gene level coefficients for multivariate analysis. The model including environmental exposures, phase 1 SNPs and NER capacity had the best fit (AIC=93.7). NER capacity itself was affected by a polymorphism in the methylenetetrahydrofolate reductase gene. Conclusion: We observed a high level of PAH-DNA adducts with great inter-individual variation, which could be best explained by a combination of environmental factors, number of polymorphisms in phase 1 genes and DNA repair capacity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2646. doi:1538-7445.AM2012-2646