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”)获得者牵头的独立申请，本提案针对NIH计划公告PA-09-234(“饮食、表观遗传学事件和癌症预防”)提出了结直肠癌表观遗传学和流行病学的假说。在美国，结直肠癌是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一个标志。此外，非癌症细胞中的DNA甲基化改变(如印迹丢失)可能更容易导致癌症的发生。重要的是，表观遗传改变，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族维生素等一碳营养素)可能会影响细胞的表观遗传状态。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展和进展非常重要，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，我们将利用两项大型前瞻性队列研究的资源，即护士健康研究(NHS)和卫生专业人员后续研究(HPFS)。这两项队列研究都提供了20年期间的饮食数据、血细胞DNA、长期生存数据以及结直肠癌的石蜡包埋组织。我们预计到2012年，在这些队列中发生的结直肠癌病例将超过4500例，其中，石蜡包埋的组织材料将在超过3000例病例中可用。我们建议研究饮食中单一碳素营养素的摄入量与酒精、结直肠癌风险、细胞表观遗传学改变和临床结果之间的相互关系。此外，我们将利用从队列中1000例结直肠癌全基因组表达谱得到的数据(一直在单独的资金支持下进行)来发现与结直肠癌中异常的单碳代谢以及特定的表观基因组异常潜在相关的基因。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异常以及肿瘤细胞全基因组表达模式之间的关系。通过更好地了解表观遗传学的致癌机制，可以为结直肠癌的发病率和死亡率提出预防措施。 公共卫生相关性：预防结直肠癌的发生和死亡对公众非常重要，因为每年约有140,000美国人罹患结直肠癌，约50,000人死于这种疾病。我们建议研究可改变的饮食因素、结直肠癌风险、细胞表观遗传学改变和患者存活率之间的关系。通过更好地了解结直肠癌发生发展的表观遗传学机制，我们可以为饮食建议提供科学依据，并帮助优化预防策略。

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.