Dietary Carcinogens for Colorectal Cancer

结直肠癌的膳食致癌物

基本信息

批准号：
10401445
负责人：
Yong Li
金额：
$ 35.87万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-10-16 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401445
关键词：
Aberrant crypt foci Address Alleles American Animal Model Aromatic Hydrocarbons Benign Benzo(a)pyrene Binding Biological Cancer Etiology Carcinogens Carcinoma Cell physiology Cells Cessation of life Chronic Clinical Colon Colonic Adenoma Colonic Neoplasms Colonic inflammation Colorectal Colorectal Cancer Consensus DNA Sequence Alteration Data Development Disease Dose Environment Environmental Carcinogens Environmental Exposure Environmental Risk Factor Epidemiology Epigenetic Process Evolution Exposure to Food Frequencies Fruit Future General Population Genetic Genetic Diseases Genetic Polymorphism Genetic Predisposition to Disease Genetic Risk Genetic Variation Genome Heterozygote Homozygote Human Hydrocarbons In Vitro Incidence Individual Ingestion Inhalation Injury Intervention Investigation Link Malignant Neoplasms Malignant neoplasm of lung Mediating Messenger RNA Molecular Mus Mutant Strains Mice Mutation Nucleotides Odds Ratio Oral Orthologous Gene Pathogenesis Patients Penetrance Persons Polyadenylation Population Population Study Populations at Risk Positioning Attribute Predisposition Prevention strategy Preventive Public Health Receptor Signaling Regimen Reporting Research Risk Risk Assessment Risk Factors Role Route Signal Transduction Single Nucleotide Polymorphism Sodium Dextran Sulfate Susceptibility Gene TP53 gene Therapeutic Toxic effect Toxicology Tumor Promoters United States Untranslated RNA Ursidae Family Variant adenoma attributable mortality base carcinogenicity colon carcinogenesis colon tumorigenesis colorectal cancer prevention colorectal cancer risk dietary dietary carcinogenesis drinking water gene interaction genetic risk factor genetic variant in vivo mouse genome mutant next generation novel novel diagnostics prospective receptor response risk variant

项目摘要

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.

项目概要结直肠癌是美国癌症相关死亡的第二大原因。大约三分之一结直肠癌死亡可归因于遗传因素，但高外显率的种系变异使结直肠癌风险增加 3 倍以上（如 APC）仅占所有病例的约 5%。广阔的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。对低渗透率的广泛调查结直肠癌的多因素易感性现已开始显现，对了解疾病发病机制并制定新的诊断、预防和治疗策略。然而，饮食致癌物等环境暴露在结直肠癌及其发病中的作用与遗传易感性等位基因的相互作用尚不清楚。流行病学估计表明约 70% 的结直肠癌可归因于摄入致癌物质。苯并[a]芘 (BaP) 是一种普遍存在的物质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直肠癌。位于 p53 基因多腺苷酸化信号中的一种新型非编码遗传变异是最近被确定为结直肠癌的低外显率遗传风险变异。该p53变体定位于它在结直肠癌易感等位基因中是独一无二的，因为它是非编码的并且出现频率较高。一般人群中大约有五分之一（即超过 600 万美国人和全世界 1 亿人）携带此病毒突变体。我们拥有令人信服的初步数据，建立了 BaP 暴露与增加之间的联系。结直肠癌的发病率与 p53 多腺苷酸化信号变异相关。根据这一证据，我们假设环境 BaP 和低外显率易感性等位基因的相互作用是结直肠癌发病机制的重要决定因素。在此应用中，我们提出了 2 个具体目标来研究饮食致癌物与结直肠癌低外显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 的结肠癌发生谱并表征 p53 中的结肠肿瘤发生率暴露于 BaP 的多聚腺苷酸信号突变小鼠。在目标 2 中，我们将剖析分子机制由此可见，BaP 暴露会导致人和小鼠细胞以及患有以下疾病的小鼠发生结肠癌： p53 多腺苷酸化信号变体。随着这个项目的完成，我们将把 BaP 定义为一种小说环境危险因素，并且是易感人群结直肠癌的潜在完全致癌物。我们将了解 p53 变体在 p53 介导的细胞过程中的体内和体外功能以及 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中。