Dietary Carcinogens and Cancer Risk: Findings From Japanese Studies

Background: Red meat and processed meat consumption are established risk factors for colorectal cancer. One hypothesized mechanism for this association is through exposure to heterocyclic aromatic amines (HAAs), which are formed when meat is cooked at high temperature for a long duration. Although they are mutagenic and carcinogenic in nonhuman primates, the findings of epidemiologic studies that have specifically examined the association between HAA intake and colorectal cancer risk have been inconsistent. Moreover, since N-acetyltransferase 2 (NAT2) has been shown to play a critical role in the bioactivation of HAAs, an interaction between HAA intake and NAT2 on colorectal cancer has been hypothesized and the findings in the previous studies have been inconsistent. Aim: To investigate the association of meat- and fish-derived HAA intake, which were estimated by our validated food frequency questionnaire and population-specific data on HAA contents in meat and fish items with the risk of colorectal adenoma, precursor of colorectal cancer, among middle-aged and elderly Japanese in Japan and Japanese Brazilians in Sao Paulo. In addition, to test the modifying effect of NAT2 on the association of HAA intake on colorectal adenoma risk. Methods: Tokyo adenoma study includes 738 patients with adenoma and 697 controls who underwent total colonoscopy in National Cancer Center, Japan. Brazil adenoma study includes 316 patients with adenoma and 403 controls who underwent total colonoscopy in 2 hospitals in Sao Paulo. HAA intake was estimated from meat and fish intake based on an HAA database that was validated against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) values measured in human hair. NAT2 acetylation genotype was inferred using 2 SNPs in the NAT2 gene. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence interval (CI) for the association between HAA intake and colorectal adenoma risk after adjusting for potential confounders. Results: Tokyo adenoma study showed that high intake of 2-amino-3,4-dimethylimidazo[4, 5-f]quinoline (MeIQ) and total HAA was significantly associated with an increased risk of colorectal adenoma in women but not in men. No clear association with PhIP or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intakes and no effect modification by NAT2 genotype was observed. Brazil adenoma study found no association for HAAs and no effect modification by NAT2 genotype. Conclusion: Tokyo Adenoma Study suggests that high MeIQ and total HAA intakes are positively associated with colorectal adenoma risk among Japanese women in Japan. However, Brazil adenoma study failed to observe positive associations. The possible explanations of inconsistent findings and the difficulty of the studies will be discussed.