Dietary Carcinogens for Colorectal Cancer

项目摘要 在美国，结直肠癌是癌症相关死亡的第二大原因。大约三分之一的人 结直肠癌死亡可归因于遗传因素，但高外显性，生殖系变异， 结直肠癌风险增加3倍以上(如APC)仅占所有病例的5%左右。浩瀚无边 大多数结直肠癌涉及基因与环境的相互作用，特别是在 涉及常见低外显率变体的实例。对低外显率的广泛调查， 结直肠癌的多因素易感性现在开始结出硕果，这对 了解疾病的发病机制，开发新的诊断、预防和治疗策略。 然而，饮食致癌物等环境暴露在结直肠癌中的作用及其 与遗传易感等位基因的相互作用还不是很清楚。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质。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，与增加患上 结直肠癌。位于p53基因多聚腺苷信号中的一个新的非编码遗传变异体是 最近被确定为结直肠癌的低外显性遗传风险变异。这个P53变种被定位在 这在结直肠癌易感等位基因中是独一无二的，因为它是非编码的，出现频率更高。 在普通人口中，大约每50人中就有1人携带这种病毒，即超过600万美国人和全球1亿人。 变种人。我们有令人信服的初步数据建立了暴露于苯并苯和增加的 结直肠癌的发病率与P53多聚腺苷信号变异有关。基于这一证据， 我们假设环境BaP和低外显性易感等位基因的交互作用是 结直肠癌发病的重要决定因素。在这个应用中，我们提出了两个具体的目标来研究 饮食致癌物质与结直肠癌低外显性基因变异之间的分子相互作用。 在目标1中，我们将定义BaP的结肠癌发生情况，并表征P53中的结肠癌发病率。 多聚腺苷信号突变小鼠暴露于苯并[a][a]。在目标2中，我们将剖析分子机制。 因此，暴露于BaP可促进人和小鼠细胞以及患有 P53多聚腺苷信号变异体。随着这个项目的完成，我们将把Bap定义为一部小说 环境风险因素，在易感人群中可能是结直肠癌的完全致癌物。 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以及在 BaP诱导的结肠肿瘤形成，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.