Nutrition, Metabolism, and Cancer

叶酸和一碳代谢叶酸是一碳(甲基)代谢所必需的，一碳(甲基)代谢是DNA合成、修复和甲基化的生化途径。有效的单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统计学上显著增加100-200%的风险和低血清或红细胞叶酸相关，仅增加20%-60%。这一模式表明，循环中的同型半胱氨酸可能是组织中叶酸不足的综合衡量标准，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的两个常见多态的变异形式和蛋氨酸合成酶基因的一个常见多态都与宫颈癌风险增加有关。风险通常会随着变异基因拷贝的增加而增加。这些结果表明，单碳代谢途径中的遗传变异和微量营养素不足都可能导致宫颈癌风险的增加。目前正在对途径基因的其他多态进行分析。我们还在探索一碳代谢在前列腺癌、肺癌、结直肠癌和卵巢癌(PLCO)队列中结直肠癌和乳腺癌的病因中的作用。大量发现的晚期结直肠腺瘤(1200例)将使我们能够系统地寻找关键的一碳代谢基因的多态变异的主要影响，使用间隔多态作为遗传变化的生物标记物。蔬菜、水果和类胡萝卜素的保护作用经常被吹捧为饮食和癌症流行病学研究中最有说服力的发现，证据最强的是肺脏。

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