Dietary Methyl Content, Epigenetics and Breast Cancer

描述（由申请人提供）：大多数前瞻性流行病学研究表明，低叶酸和高酒精的饮食显著增加乳腺癌（BC）的风险，使甲基（或一碳）缺乏饮食成为BC的少数可改变的风险因素之一。同样，在长岛乳腺癌研究项目（LIBCSP）中，一项基于人群的病例对照研究发现，低膳食摄入或叶酸代谢基因MTHFR变异基因型导致的叶酸水平低于最佳水平，会增加BC的风险。这些发现强烈暗示了一碳代谢和BC之间的因果关系。然而，这种关联的机制还不清楚。乳腺癌是一种异常的遗传以及表观遗传变化的表现。一碳代谢通过在DMA甲基化和DMA合成中发挥关键作用而促进遗传和表观遗传过程之间的串扰。本研究的目的是探讨一碳代谢是否通过表观遗传过程影响乳腺癌的发生。具体来说，我们将研究膳食摄入的一碳相关的微量营养素/化合物（如叶酸，蛋氨酸，胆碱，维生素B2，B6，B12，酒精等）的关系，全球低甲基化和启动子高甲基化的程度BC相关基因。我们将研究编码一碳代谢酶的基因多态性是否会改变全局和启动子甲基化的程度/模式。我们建议利用基于人口的LIBCSP的资源，使拟议的研究高度可行和具有成本效益。更好地了解导致BC发展的病因学因素有助于确定针对该疾病的预防策略。由于表观遗传改变是可逆的，并且发生在癌症发展的早期，因此它们是预防癌症的有希望的靶点。确定决定甲基化模式的因素可以为疾病的机制提供证据，并确定可以提供适当饮食干预的风险人群。

DESCRIPTION (provided by applicant): Most prospective epidemiologic studies have shown that a diet that is low in folate and high in alcohol significantly increases the risk of breast cancer (BC), making the methyl (or one-carbon)-deficient diet one of the few modifiable risk factors for BC. Consistently, in the Long Island Breast Cancer Study Project (LIBCSP), a population-based case-control investigation, suboptimal levels of folate, either from low dietary intake or having the variant genotype of the folate-metabolizing gene, MTHFR, confer increased risk of BC. These findings strongly implicate a causal relationship between one-carbon metabolism and BC. However, the mechanism of this association is not well understood. Breast Cancer is a manifestation of abnormal genetic as well as epigenetic changes. One-carbon metabolism facilitates the cross talk between genetic and epigenetic processes by playing critical roles in both DMA methylation and DMA synthesis. The purpose of this proposed study is to investigate whether one-carbon metabolism influences breast carcinogenesis through an epigenetic process. Specifically, we will examine the dietary intake of one-carbon-related micronutrients/compounds (e.g. folate, methionine, choline, vitamins B2, B6, B12, alcohol, etc) in relation to the degree of global hypomethylation and promoter hypermethylation of BC-related genes. We will investigate whether polymorphisms in genes encoding one-carbon-metabolizing enzymes modify the degree/patterns of global and promoter methylation. We propose to utilize the resources of the population- based LIBCSP, making the proposed study highly feasible and cost-effective. A better understanding of the etiological factors contributing to the development of BC could aid in identification of a preventive strategy against the disease. Since epigenetic alterations are reversible and occur early in cancer development, they are promising targets for cancer prevention. To identify the factors that determine the patterns of methylation can provide evidence for the mechanisms of the disease as well as identify at-risk populations in which appropriate diet-based intervention can be provided.