Epigenetic Events and Colorectal Cancer Epidemiology

表观遗传学事件和结直肠癌流行病学

• 批准号: 8101809
• 负责人: Shuji Ogino
• 金额: $ 56.39万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101809
• 关键词: Aberrant DNA Methylation; Address; Affect; Alcohol consumption; Alcohols; American; Award; Blood Cells; Cancer Etiology; Carbon; Cells; Cessation of life; Chemoprevention; Clinical; Cohort Studies; Colorectal; Colorectal Cancer; Complement; CpG Island Methylator Phenotype; DNA; DNA Methylation; Data; Development; Diet; Dietary Factors; Dietary intake; Disease; Epidemiology; Epigenetic Process; Event; Excision; Funding; Gene Expression; Gene Expression Regulation; Genes; Genomics; Health Professional; Incidence; Individual; Insulin-Like Growth Factor II; Intake; Investments; Long Interspersed Nucleotide Elements; Malignant Neoplasms; Measures; Metabolism; Molecular Epidemiology; Molecular Profiling; NIH Program Announcements; Nurses' Health Study; Nutrient; Outcome; Paraffin Embedding; Patients; Pattern; Positioning Attribute; Prevention strategy; Preventive; Reaction; Recommendation; Research; Resources; Tissues; United States; Vitamin B Complex; base; cancer epidemiology; cancer prevention; cancer risk; carcinogenesis; cohort; colorectal cancer prevention; cost; epigenomics; follow-up; gene discovery; genome-wide; imprint; improved; interest; mortality; neoplastic cell; prospective; public health relevance; response

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.

描述（由申请人提供）：作为NCI K 07奖（“结直肠癌分子流行病学”）获得者领导的第一个独立申请，该提案针对NIH计划公告PA- 09-234（“饮食，表观遗传事件和癌症预防”）提出了结直肠癌表观遗传学和流行病学的假设。结直肠癌是美国癌症死亡的第二大原因。异常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（如印记丢失）可能易患癌症。重要的是，包括DNA甲基化改变在内的表观遗传变化是可逆的，因此可以成为治疗或化学预防的靶点。越来越多的证据表明，饮食因素（例如，酒精和一碳营养素如B族维生素）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）和卫生专业人员随访研究（HPFS）。两项队列研究都提供了20年的饮食数据、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例结肠直肠癌病例，其中，石蜡包埋组织材料将在超过3000例病例中提供。我们建议检查饮食中一碳营养素和酒精的摄入量，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例结直肠癌的全基因组表达谱数据（该数据一直在单独的资金支持下进行），以发现与结直肠癌中异常一碳代谢以及特定表观基因组畸变可能相关的基因。因此，我们处于一个独特的位置，以检查可改变的饮食因素，表观遗传和表观基因组畸变，肿瘤细胞的全基因组表达模式之间的关系。通过更好地了解癌症发生的表观遗传机制，我们可以提出预防措施，从结直肠癌的发病率和死亡率。 公共卫生关系：预防结直肠癌的发生和死亡具有极大的公共利益，因为每年约有140，000名美国人患结直肠癌并且约有50，000人死于该疾病。我们建议检查可改变的饮食因素，结直肠癌的风险，细胞表观遗传变化和患者生存之间的关系。通过更好地了解结直肠癌发展和进展的表观遗传机制，我们可以为饮食建议提供科学依据，并帮助优化预防策略。