Dietary Carcinogens for Colorectal Cancer

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Project Summary Colorectal cancer is the second leading cause of cancer-related death in the United States. About one third of colorectal cancer deaths are attributable to inherited factors, yet high-penetrance, germline variants that increase colorectal cancer risk more than 3-fold (like APC) only account for ~5% of all cases. The vast majority of colorectal cancers involve the interaction of genes with the environment, particularly in instances involving common low-penetrance variants. Extensive investigation into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease pathogenesis and developing new diagnostic, preventive, and therapeutic strategies. However, the role of environmental exposure such as dietary carcinogens in colorectal cancer and its interaction with genetic susceptibility alleles are not well understood. Epidemiological estimates suggest that ~70% of colorectal cancers are attributable to carcinogens via ingestion. Benzo[a]pyrene (BaP), a ubiquitous environmental hydrocarbon found in burnt foods and drinking water, has been associated with increased risk of colorectal cancer. A novel noncoding genetic variant located in the polyadenylation signal of the p53 gene was recently identified as a low-penetrance genetic risk variant in colorectal cancer. This p53 variant is positioned uniquely among colorectal cancer-susceptibility alleles in that it is noncoding and present at higher frequency. About 1 in 50 in general populations, i.e., over 6 million Americans and 100 million people worldwide, carry this mutant. We have compelling preliminary data establishing a link between exposure to BaP and increased colorectal cancer incidence associated with the p53 polyadenylation signal variant. Based on this evidence, we hypothesize that the interaction of environmental BaP and low-penetrance susceptibility alleles is a significant determinant of CRC pathogenesis. In this application, we propose 2 specific aims to study the molecular interactions between a dietary carcinogen and a low-penetrance genetic variant of colorectal cancer. In Aim 1, we will define the colon carcinogenesis profile of BaP and characterize colon tumor incidence in p53 polyadenylation signal mutant mice exposed to BaP. In Aim 2, we will dissect the molecular mechanisms whereby BaP exposure contributes to colon carcinogenesis in human and mouse cells and in mice with the p53 polyadenylation signal variant. With the completion of this project, we will have defined BaP as a novel environmental risk factor and potentially a complete carcinogen for colorectal cancer in susceptible individuals. We will understand the in vivo and in vitro function of the p53 variant in p53-mediated cellular processes and in BaP-induced colon tumorigenesis and be able to expand these findings to future patient studies.