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

叶酸和一碳代谢叶酸对于单碳（甲基）代谢，这是参与DNA合成，修复和甲基化的生化途径所必需的。有效的一碳代谢还需要维生素B-6和B-12，核黄素和10-20酶的最佳活性。在一项基于社区的侵入性宫颈癌的病例对照研究中，我们表明高血清同型半胱氨酸与统计学上显着的100-200％的风险和低血清或红细胞叶酸相关，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或一种破坏单碳代谢的生物标志物的整合度量。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蛋氨酸合酶基因中常见的多态性均与宫颈癌升高有关。随着变体基因副本的增加，风险通常增加。这些结果表明，单碳代谢途径的遗传变异性和微量营养素不足都可以导致宫颈癌的风险增加。 现在正在测定途径基因中的其他多态性。 我们还探索了单碳代谢在前列腺，肺，结直肠癌和卵巢癌（PLCO）同伴中结直肠癌和乳腺癌病因中的作用。 确定的大量晚期结直肠腺瘤（1200）将使我们能够使用间隔的多态性作为遗传变化的生物标志物系统地搜索关键的单碳代谢基因中多态性变化的主要影响。 同型半胱氨酸的循环水平与各种叶酸形式和基因型之间的关系也将得到探索。蔬菜，水果和类胡萝卜素通常将蔬菜和水果的保护作用经常被吹捧为最有说服力的发现，可以从饮食和癌症的表现上有很强的证据，并具有最有证据