Diet, Genetics, Epigenetics and Colorectal Adenoma Risk.

描述（由申请人提供）：这个癌症预防、控制和人口科学职业发展奖将为Shrubsole博士和她的导师提供详细的策略，帮助Shrubsole博士实现作为癌症研究人员的独立性，特别是结肠直肠癌。在本奖项的培训计划中，将通过课程学习、研讨会、全国会议和导师定期会议等方式，获得结直肠癌生物学、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。这些技能将转化为研究检查生活方式，遗传和表观遗传易感性和结直肠腺瘤的风险。叶酸，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。同时，越来越多的证据表明，异常DNA甲基化，如肿瘤抑制基因的高甲基化，在结直肠癌和腺瘤中都增加了。为了进一步了解饮食和DNA甲基化在腺瘤发展中的作用，需要进行流行病学研究，研究这些因素和参与DNA甲基化相关途径的基因的作用。因此，本课题的研究目标是在一项大型结直肠腺瘤病例对照研究（n=3000）中评估与甲基群摄入（叶酸、蛋氨酸、维生素B6、维生素B12）、参与甲基转移的基因多态性（MTHFR、DNMT1、DNMT3A）、正常直肠黏膜抑癌基因启动子甲基化（APC、RASSF1 a, n=4DO）以及这些因素的综合相关性相关的风险。将正常直肠粘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甲基化表型在正常直肠粘膜中作为腺瘤风险标志物的潜在效用。主要研究支持将来自候选人主要导师郑伟博士现有的分子流行病学研究。这项工作将扩展我们对DNA甲基化与腺瘤风险之间的联系以及与遗传易感性的相互作用的理解。它也可能有助于确定结直肠腺瘤的高危人群。该CDA的研究工作将作为候选人在该奖项的后几年提交有竞争力的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.