Epigenetic Events and Colorectal Cancer Epidemiology

描述（由申请人提供）：作为第一个由NCI K07奖（“结直肠癌分子流行病学”）获得者领导的独立申请，该提案针对美国国立卫生研究院项目公告PA- 09-234（“饮食，表观遗传事件和癌症预防”），探讨了结直肠癌表观遗传学和流行病学的假设。结直肠癌是美国癌症死亡的第二大原因。异常的DNA甲基化模式是包括结直肠癌在内的大多数癌症的标志。此外，非癌细胞中的DNA甲基化改变（如印迹的丢失）可能易导致癌症的发展。重要的是，表观遗传变化，包括DNA甲基化改变，是可逆的，因此可以成为治疗或化学预防的目标。越来越多的证据表明，饮食因素（如酒精和B族维生素等单碳营养素）可能影响细胞表观遗传状态。研究饮食因素如何影响表观遗传改变对于更好地了解结直肠癌的发生和进展具有重要意义，这可以为饮食建议提供科学依据，并有助于优化预防策略。为此，我们将利用两个大型前瞻性队列研究的资源，护士健康研究（NHS）和卫生专业人员随访研究（HPFS）。两项队列研究都提供了20年期间的饮食数据、血细胞DNA、长期生存数据和结直肠癌石蜡包埋组织。我们预计到2012年，这些队列中将有超过4500例结直肠癌病例，其中石蜡包埋组织材料将用于超过3000例病例。我们建议研究饮食中一碳营养素摄入量与酒精、结直肠癌风险、细胞表观遗传变化和临床结果之间的相互关系。此外，我们将利用队列中1000个结直肠癌的全基因组表达谱数据（该数据已在单独的资金支持下进行）来发现可能与结直肠癌异常单碳代谢以及特定表观基因组畸变相关的基因。因此，我们处于一个独特的位置来研究可改变的饮食因素、表观遗传和表观基因组畸变以及肿瘤细胞全基因组表达模式之间的关系。通过对癌变的表观遗传机制的深入了解，我们可以对结直肠癌的发病率和死亡率提出预防措施。

DESCRIPTION (provided by applicant): As the first independent application led by a recipient of NCI K07 Award ("Molecular Epidemiology of Colorectal Cancer"), this proposal addresses hypotheses in epigenetics and epidemiology of colorectal cancer, in response to NIH Program Announcement PA- 09-234 ("Diet, Epigenetic Events, and Cancer Prevention"). Colorectal cancer is the second leading cause of cancer death in the United States. Abnormal DNA methylation patterns are a hallmark of most cancers including colorectal cancer. Furthermore, DNA methylation alterations (such as loss of imprinting) in non-cancerous cells may predispose to cancer development. Importantly, epigenetic changes, including DNA methylation alterations, are reversible and thus can be targets for therapy or chemoprevention. Accumulating evidence suggests that dietary factors (e.g., alcohol and one-carbon nutrients such as B vitamins) may affect cellular epigenetic status. Examining how dietary factors influence epigenetic alterations is important for better understanding of colorectal cancer development and progression, which can provide a scientific basis for dietary recommendations and help optimize preventive strategies. For that purpose, we will utilize the resources of two large prospective cohort studies, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Both cohort studies provide dietary data over a 20-year period, DNA from blood cells, long-term survival data, and paraffin-embedded tissue of colorectal cancers. We anticipate over 4500 incident colorectal cancer cases up to 2012 in these cohorts, and among those, paraffin-embedded tissue materials will be available in over 3000 cases. We propose to examine the interrelationship between intake of dietary one-carbon nutrients and alcohol, colorectal cancer risk, cellular epigenetic changes, and clinical outcome. In addition, we will utilize data resulting from genome-wide expression profiling of 1000 colorectal cancers in the cohorts (which has been ongoing with separate funding supports) to discover genes potentially related to abnormal one-carbon metabolism as well as specific epigenomic aberrations in colorectal cancer. Thus, we are in a unique position to examine the relations between modifiable dietary factors, epigenetic and epigenomic aberrations, and genome-wide expression patterns in tumor cells. Through better understanding of epigenetic mechanisms of carcinogenesis, we can propose preventive measures for the incidence and mortality from colorectal cancer. PUBLIC HEALTH RELEVANCE: Prevention of colorectal cancer occurrence and mortality is of great public interest, because approximately 140,000 Americans develop colorectal cancer and approximately 50,000 individuals die from the disease every year. We propose to examine the relations between modifiable dietary factors, colorectal cancer risk, cellular epigenetic changes, and patient survival. Through better understanding of epigenetic mechanisms of colorectal cancer development and progression, we can provide a scientific basis for dietary recommendations and help optimize preventive strategies.