Folate Polymorphisms, Dietary Folate and Prostate Cancer

描述（由申请人提供）： 对前列腺癌可改变的风险因素的研究集中在一些饮食成分上，包括脂肪，肉类和微量营养素。然而，一种营养素已被证明会影响许多其他癌症的风险，而在前列腺癌中几乎没有调查，那就是叶酸。这种维生素在DNA合成，修复和甲基化中起着至关重要的作用，叶酸代谢的不平衡会增加遗传不稳定性并促进致癌作用。叶酸代谢紊乱可能是由于叶酸代谢酶的遗传多态性或该过程所需营养素的饮食摄入不足。 在这项研究中，我们将确定叶酸代谢的改变，无论是遗传还是饮食因素，是否与前列腺癌的风险有关。将进行一项嵌套在正在进行的美国癌症协会CPS-II队列中的病例对照研究。将分析1209名前列腺癌患者和1209名匹配对照的DNA样本，以确定编码叶酸代谢蛋白的7个基因中9个多态性的基因型。在癌症诊断之前收集的饮食信息将被分析，以确定影响叶酸代谢的五种营养素的水平。将应用逻辑回归模型来确定每个遗传和饮食变量的主要影响。根据叶酸和高或低酒精摄入量的四分位数分层将用于测量相互作用的营养素对各种多态性的影响。最后，将使用新开发的技术研究基因-基因相互作用，根据男性的变异等位基因数量将其分为高风险和低风险基因型。这项研究的结果预计将表明叶酸对前列腺癌的重要性，以及改变叶酸摄入量是否可以改变叶酸代谢途径中与遗传变异相关的风险。

DESCRIPTION (provided by applicant): The search for modifiable risk factors for prostate cancer has focused on a number of dietary components, including fat, meats, and micronutrients. However, one nutrient that has been shown to influence risk for a number of other cancers for which there has been little investigation of in prostate cancer is folate. This vitamin plays an essential role in DNA synthesis, repair and methylation, and imbalances in folate metabolism increase genetic instability and facilitate carcinogenesis. Perturbations in folate metabolism can result from genetic polymorphisms in folate-metabolizing enzymes or inadequate dietary consumption of nutrients required for this process. In this study, we will determine whether altered folate metabolism, resulting from either genetic or dietary factors, is associated with prostate cancer risk. A case-control study, nested in the ongoing American Cancer Society CPS-II cohort, will be conducted to do this. DNA samples from 1209 men with prostate cancer and 1209 matched controls will be analyzed to determine the genotype of nine polymorphisms in seven genes encoding folate-metabolizing proteins. Dietary information collected prior to the cancer diagnosis will be analyzed to determine levels of five nutrients that influence folate metabolism. Logistic regression models will be applied to determine the main effects of each of the genetic and dietary variables. Stratification according to quartiles of folate and high or low alcohol intake will be used to measure the influence of interacting nutrients on the various polymorphisms. Finally, gene-gene interactions will be studied using newly developed techniques to classify men into high- and low-risk genotypes depending on the number of variant alleles they have. The results of this study are expected to indicate the importance of folate for prostate cancer and whether changing folate consumption can modify the risk associated with genetic variants in the pathway for folate metabolism.