Diet, Genetics, Epigenetics and Colorectal Adenoma Risk.

描述(由申请者提供)：这一癌症预防、控制和人口科学职业发展奖将为舒博索尔博士和她的导师们提供一个详细的策略，帮助舒博索尔博士作为一名癌症研究人员实现独立，特别是结直肠癌。结直肠癌生物学、表观遗传学和分子/遗传流行病学方法方面的新知识和技能将在该奖项的培训计划中获得，包括通过课程作业、研讨会、全国会议和与导师的定期会议。这些技能将被转化为研究生活方式、遗传和表观遗传易感性以及结直肠腺瘤风险。叶酸是一种B族维生素，对蛋氨酸的再生至关重要，蛋氨酸是DMA甲基化的甲基供体。低叶酸和/或蛋氨酸在结直肠腺瘤/癌症风险中的作用的证据正在积累。与此同时，越来越多的证据表明，异常的DNA甲基化，如抑癌基因的超甲基化，在结直肠癌和腺瘤中都会增加。为了促进我们对饮食和DNA甲基化在腺瘤发生中的作用的理解，需要进行流行病学研究，以检验这些因素和参与DNA甲基化相关途径的基因的作用。因此，这项建议的研究目标是在一项大型结直肠腺瘤病例对照研究中(n=3000)评估与甲基摄入(叶酸、蛋氨酸、维生素B6、维生素B12)、与甲基转移相关的基因多态性(MTHFR、DNMT1、DNMT3A)、正常直肠黏膜中肿瘤抑制基因的启动子甲基化(APC、RASSF1A，n=4DO)以及这些因素的联合关联。将正常直肠黏膜的甲基化表型与腺瘤的甲基化表型进行比较。此外，将通过研究影响甲基化水平的因素来评估正常直肠黏膜中甲基化表型作为腺瘤风险标志的潜在实用性。主要的研究支持将来自候选人的主要导师魏征博士现有的分子流行病学研究。这项工作将扩大我们对DNA甲基化和腺瘤风险之间的联系以及与遗传易感性之间的相互作用的理解。它还可能有助于确定结直肠腺瘤的高危人群。本次CDA的研究工作将作为候选人在该奖项后期提交竞争性R01提案的基础。

DESCRIPTION (provided by applicant): This Cancer Prevention, Control, and Population Sciences Career Development Award will provide Dr. Shrubsole and her mentors a detailed strategy for Dr. Shrubsole to achieve independence as a cancer researcher, particularly colorectal cancer. New knowledge and skills in colorectal cancer biology, epigenetics, and molecular/genetic epidemiology methods will be obtained in the training plan of the award including through coursework, seminars, national meetings, and regular meetings with mentors. These skills will be translated to research examining lifestyle, genetic and epigenetic susceptibility, and colorectal adenoma risk. Folate, a B vitamin is essential for regenerating methionine, the methyl donor for DMA methylation. Evidence of a role of low folate and/or methionine in colorectal adenoma/cancer risk is accumulating. Simultaneously, there is increasing evidence that aberrant DNA methylation, such as hypermethylation of tumor suppressor genes, is increased in both colorectal cancers and adenomas. To advance our understanding of the role of diet and DNA methylation in adenoma development, epidemiologic studies examining the role of these factors and genes involved in DNA methylation associated pathways are needed. Thus, the research goals of this proposal are to evaluate in a large colorectal adenoma case-control study (n=3000) risk associated with methyl-group intake (folate, methionine, vitamin B6, vitamin B12), polymorphisms in genes involved in methyl-group transfer (MTHFR, DNMT1, DNMT3A), promoter methylation of tumor suppressor genes in normal rectal mucosa (APC, RASSF1 A, n=4DO), and the combined association of these factors. The methylation phenotype in normal rectal mucosa will be compared with methylation phenotype in adenomas. Additionally, the potential utility of methylation phenotype in normal rectal mucosa as a marker of adenoma risk will be evaluated by studying factors that affect level of methylation. Primary research support will come from an existing molecular epidemiology study of the candidate's primary mentor, Dr. Wei Zheng. This work will extend our understanding of links between DNA methylation and adenoma risk as well as interactions with genetic susceptibility. It may also serve to help identify high-risk populations for colorectal adenoma. The research work in this CDA will serve as the basis for submission of competitive R01 proposals by the candidate in latter years of this award.