Nutrition, Metabolism, and Cancer

营养、新陈代谢和癌症

• 批准号: 10263750
• 负责人: Gretchen Gierach
• 金额: $ 31.74万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263750
• 关键词: Biochemical Pathway; Biological Assay; Biological Markers; Body of uterus; Carbon; Case-Control Studies; Categories; Cohort Studies; Colorectal Adenoma; Colorectal Cancer; Communities; DNA biosynthesis; Disease; Enzymes; Erythrocytes; Etiology; Folic Acid; Fruit; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genotype; Goals; Homocysteine; Human; Lung; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Measures; Metabolic; Metabolism; Methionine; Methylation; Methylenetetrahydrofolate reductase (NADPH); Micronutrients; Mutation; Nutritional; Papillomavirus; Pathway interactions; Pattern; Riboflavin; Risk; Role; Serum; Sexually Transmitted Diseases; Tissues; Variant; Vitamin B6; base; cancer risk; cohort; diet and cancer; epidemiology study; folic acid metabolism; fruits and vegetables; genetic variant; malignant breast neoplasm; methyl group; multidisciplinary; nutrition; protective effect; repaired

FOLATE AND ONE-CARBON METABOLISM Folate is essential for one-carbon (methyl group) metabolism, a biochemical pathway involved in DNA synthesis, repair, and methylation. Efficient one-carbon metabolism also requires vitamins B-6 and B-12, riboflavin, and optimal activity of 10-20 enzymes. In a community-based, case-control study of invasive cervical cancer, we showed that high serum homocysteine was associated with a statistically significant 100-200% increase in risk and low serum or red blood cell folate, with only a 20-60% increase. This pattern suggests that circulating homocysteine may be an integratory measure of insufficient folate in tissues or a biomarker of disruption of one-carbon metabolism. Variant forms of two common polymorphisms in the methylene tetrahydrofolate reductase gene and a common polymorphism in the methionine synthase gene were each associated with elevated cervical cancer risk. Risk generally increased as copies of the variant gene increased. These results suggest that both genetic variability in the one-carbon metabolism pathway and micronutrient inadequacy can contribute to increased risk of cervical cancer. Additional polymorphisms in pathway genes are now being assayed. We are also exploring the role of one-carbon metabolism in the etiology of both colorectal and breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) cohort. The large number of advanced colorectal adenomas (1200) identified will allow us to systematically search for main effects of polymorphic variation in key one-carbon metabolism genes, using spaced polymorphisms as biomarkers of genetic change. The relationships among circulating levels of homocysteine and various folate forms and genotype will also be explored.VEGETABLES, FRUITS, AND CAROTENOIDS The protective effect of vegetables and fruits is frequently touted as the most persuasive finding to emerge from epidemiologic studies of diet and cancer, with evidence strongest for lung

叶酸与一碳代谢 叶酸对一碳（甲基）代谢至关重要，这是一种参与DNA合成，修复和甲基化的生化途径。有效的一碳代谢还需要维生素B-6和B-12、核黄素以及10-20种酶的最佳活性。在一项以社区为基础的浸润性宫颈癌病例对照研究中，我们发现高血清同型半胱氨酸与风险增加100-200%具有统计学意义，而低血清或红细胞叶酸仅增加20-60%。 这种模式表明，循环同型半胱氨酸可能是组织中叶酸不足的综合指标，也可能是一碳代谢中断的生物标志物。亚甲基四氢叶酸还原酶基因中两种常见多态性的变异形式和甲硫氨酸合酶基因中一种常见多态性均与宫颈癌风险升高相关。风险通常随着变异基因拷贝的增加而增加。这些结果表明，一碳代谢途径的遗传变异和微量营养素不足都可能导致宫颈癌风险增加。 目前正在检测途径基因的其他多态性。 我们还在前列腺癌、肺癌、结直肠癌和卵巢癌（PLCO）队列中探索一碳代谢在结直肠癌和乳腺癌病因学中的作用。 大量的晚期结直肠腺瘤（1200）的确定将使我们能够系统地搜索关键的一碳代谢基因的多态性变异的主要影响，使用间隔多态性作为遗传变化的生物标志物。 循环中同型半胱氨酸水平与各种叶酸形式和基因型之间的关系也将被探讨。蔬菜、水果和类胡萝卜素 蔬菜和水果的保护作用经常被吹捧为从饮食和癌症的流行病学研究中出现的最有说服力的发现，