Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer

Anne M.J Gilsing,Laura Burdett,Sonja I Berndt,Joel L Weissfeld,Elizabeth H Ruder,Leah M Ferrucci,Barry I Graubard,Rashmi Sinha,Amanda J Cross

doi:10.1093/carcin/bgs158

Abstract

Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P(interaction) = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11-1.85, P(trend) = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30-0.84, P(trend) = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.

Highlights

Experimental evidence suggests that the carcinogenic potential of several meat-specific mutagens may be one of the underlying causal factors for the well-established epidemiological association between red and processed meat consumption and colorectal cancer risk [1]
Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 xenobiotic metabolizing enzymes (XME) genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
PAHs are present in cigarette smoke, in the environment and in Abbreviations: AHR, aromatic hydrocarbon receptor; B[a]P, benzo[a] pyrene; CI, confidence intervals; FFQ, food frequency questionnaire; GST, glutathione S-transferases; HCA, heterocyclic amine; MeIQx, 2-amino-3,4,8trimethylimidazo[4,5-f]quinoxaline; NAT, N-acetyltransferases; NOC, N-nitroso compound; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon; PhIP, 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine; PLCO, Prostate, Lung, Colorectal, and Ovarian; SNP, single nucleotide polymorphisms; UGT, UDP-glucuronosyltransferases; XME, xenobiotic metabolizing enzymes

Summary

Introduction

Experimental evidence suggests that the carcinogenic potential of several meat-specific mutagens may be one of the underlying causal factors for the well-established epidemiological association between red and processed meat consumption and colorectal cancer risk [1]. Heterocyclic amines (HCAs) are formed when meat is cooked welldone at high temperature [2,3]. PAHs are present in cigarette smoke, in the environment and in Abbreviations: AHR, aromatic hydrocarbon receptor; B[a]P, benzo[a] pyrene; CI, confidence intervals; FFQ, food frequency questionnaire; GST, glutathione S-transferases; HCA, heterocyclic amine; MeIQx, 2-amino-3,4,8trimethylimidazo[4,5-f]quinoxaline; NAT, N-acetyltransferases; NOC, N-nitroso compound; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon; PhIP, 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine; PLCO, Prostate, Lung, Colorectal, and Ovarian; SNP, single nucleotide polymorphisms; UGT, UDP-glucuronosyltransferases; XME, xenobiotic metabolizing enzymes. Despite the strong carcinogenic potential of HCAs, PAHs and NOCs observed in animal studies [5,6,7,8,9], evidence in humans remains inconsistent [1]

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Results

Conclusion