Abstract B129: Xenobiotic metabolizing genes, meat intake and risk of advanced colorectal adenoma

Abstracts: Frontiers in Cancer Prevention Research 2008 B129 Red meat and processed meat are positively associated with risk of colorectal neoplasia. One of the potential mechanisms underlying the association of meat with cancer is via the mutagenic action of heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) formed during high temperature cooking. Phase I xenobiotic metabolizing enzymes (XMEs) are involved in the initial steps of activation of xenobiotics to mutagenic and carcinogenic intermediates. Phase II XMEs convert original xenobiotic compounds and their phase I-activated metabolites to polar and detoxified metabolites. However, with certain compounds, such as HCAs, phase II XMEs may further activate metabolites to form other carcinogenic species. We evaluated 29 single nucleotide polymorphisms (SNPs) in several phase I (CYP1A1, CYP1B1, CYP2A6, CYP2C9, CYP2E1, and CYP3A4) and phase II (EPHX1, GSTM1, GSTM2, GSTT1, NAT1, NAT2, NQO1, SULT1A1, and SULT1A2) XME genes in relation to advanced colorectal adenoma and investigated potential effect modification by red meat, HCA, and PAH intake. All SNPS were selected based on known or suggested functional relevance and a minor allele frequency of 5% or greater in Caucasians. Participants were selected from individuals who were enrolled in the screening arm (n = 77,483) of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial between 1993 and 1999. We compared 720 cases with advanced colorectal adenoma (size of 1cm or greater, high grade dysplasia, or villous components, including tubulovillous) of the distal colon or rectum to 746 controls frequency matched on gender and ethnicity (negative for left-sided polyp by sigmoidoscopy). Using a 137-item food frequency questionnaire that included detailed questions on meat cooking methods and doneness levels in conjunction with a HCA and PAH database, we generated intake estimates of the HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), and the PAH, benzo[a]pyrene (B[a]P) in ng/day. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age, gender, and ethnicity. Tests for interaction were based on the likelihood ratio test by comparing models with and without interaction terms. Overall, we found weak or null associations between the individual XME genes or SNPs with risk of advanced colorectal adenoma. However, we observed interactions between intake of PhIP and variation in CYP1B1 (rs10012 Pinteraction = 0.019; rs1056836 Pinteraction = 0.019), and NQO1 (rs1800566 Pinteraction = 0.007) with advanced colorectal adenoma. We also found evidence of interaction with intake of B[a]P for variation in CYP1B1 (rs10012 Pinteraction = 0.005) and CYP3A4 (rs2242480 Pinteraction = 0.02). In addition, there was an interaction with intake of red meat and CYP1B1 (rs10012 Pinteraction = 0.013) and NAT1 variants (rs15561 Pinteraction = 0.037). However, when considering multiple comparisons, these interactions did not fall below a false discovery rate threshold of 0.20. Our results are intriguing and suggest that common variants in XME genes may modify the association of red meat, HCA, and PAH intake with advanced colorectal adenoma, but require confirmation in larger studies. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B129.