Dietary Carcinogens for Colorectal Cancer

项目摘要 结直肠癌是美国癌症相关死亡的第二大原因。约三分之一 结直肠癌死亡可归因于遗传因素，但高突变率，生殖系变异， 增加结肠直肠癌风险超过3倍（如APC）仅占所有病例的~5%。绝 大多数结直肠癌涉及基因与环境的相互作用，特别是在 涉及常见的低浓度变体的实例。深入调查了低浓度迷幻药 结直肠癌的多因素易感性现在开始结出果实，这对 了解疾病的发病机制，并开发新的诊断，预防和治疗策略。 然而，环境暴露如饮食致癌物在结直肠癌中的作用及其 与遗传易感性等位基因相互作用还不清楚。流行病学估计表明， 约70%的结直肠癌可归因于通过摄入致癌物。苯并[a]芘（BaP），一种普遍存在的 在烧焦的食物和饮用水中发现的环境碳氢化合物，与增加的风险有关。 结肠直肠癌一种新的非编码基因变异位于p53基因的多聚腺苷酸化信号， 最近被鉴定为结肠直肠癌的低风险遗传变异。这种p53变体定位于 在结直肠癌易感性等位基因中是独特的，因为它是非编码的，并且以更高的频率存在。 在一般人群中约为1/50，即，超过600万美国人和全世界1亿人， 变种人我们有令人信服的初步数据，建立了接触苯并[a]芘和增加 结直肠癌发病率与p53多聚腺苷酸化信号变异相关。基于这些证据， 我们假设环境BaP和低等位基因易感性的相互作用是 CRC发病机制的重要决定因素。在本申请中，我们提出了2个具体目标来研究 饮食致癌物和结肠直肠癌的低转移率遗传变异之间的分子相互作用。 在目标1中，我们将定义BaP的结肠癌发生谱，并描述p53中结肠肿瘤的发生率。 暴露于BaP的多聚腺苷酸化信号突变小鼠。在目标2中，我们将剖析 由此BaP暴露有助于人类和小鼠细胞以及具有以下特征的小鼠中的结肠癌发生： p53多聚腺苷酸化信号变体。随着这个项目的完成，我们将把BaP定义为一部小说。 环境危险因素和潜在的完整致癌物的大肠癌易感个体。 我们将了解p53变异体在p53介导的细胞过程中的体内和体外功能， BaP诱导的结肠肿瘤发生，并能够将这些发现扩展到未来的患者研究。

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.