Nutrition, Metabolism, and Cancer

营养、新陈代谢和癌症

• 批准号: 10702926
• 负责人: Gretchen Gierach
• 金额: $ 28.28万
• 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/10702926
• 关键词: Adolescent; Adult; Androgens; Asia; Asian; Asian Americans; Asian population; Biochemical Pathway; Biological; Biological Assay; Biological Markers; Blood; Body of uterus; Breast Cancer Cell; Breast Cancer Risk Factor; Breast Carcinogenesis; Cancer Etiology; Carbon; Carotenoids; Case/Control Studies; Categories; Childhood; Cohort Studies; Collaborations; Colorectal Adenoma; Colorectal Cancer; Communities; DNA biosynthesis; Data; Diagnosis; Diet; Dietary Practices; Disease; Environmental Exposure; Enzymes; Epidemiology; Erythrocytes; Estrogen Metabolism; Estrogens; Etiology; Family; Folic Acid; Follow-Up Studies; Food; Fruit; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genotype; Goals; Hawaiian; Health; Height; Homocysteine; Hormonal; Hormones; Human; Hydroxyestrones; Incidence; Individual; Indolent; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Intake; International; Interview; Japanese; Life Style; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Manuscripts; Measurement; Measures; Metabolic; Metabolism; Methionine; Methylation; Methylenetetrahydrofolate reductase (NADPH); Micronutrients; Migrant; Mothers; Mutation; NCI Center for Cancer Research; Nested Case-Control Study; Nutritional; Obesity; Papillomavirus; Participant; Pathway interactions; Pattern; Physiological; Phytoestrogens; Plasma; Play; Population; Population Study; Postmenopause; Premenopause; Principal Component Analysis; Procedures; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Proteomics; Publishing; Recording of previous events; Relative Risks; Reproducibility; Riboflavin; Risk; Risk Factors; Role; Sampling; Sensitivity and Specificity; Series; Serum; Sexually Transmitted Diseases; Smoking; Societies; Somatomedins; Testing; Tissues; Urine; Variant; Vegetables; Vitamin B6; Weight Gain; Woman; alpha-carotene; base; beta-cryptoxanthin; cancer risk; cohort; design; diet and cancer; dietary; epidemiology study; folic acid metabolism; fruits and vegetables; genetic variant; liquid chromatography mass spectroscopy; lung cancer prevention; lycopene; malignant breast neoplasm; men; methyl group; migration; multidisciplinary; nutrition; pre-clinical; prospective; prostate cancer cell; prostate cancer risk; protective effect; repaired; soy

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 and colorectal cancer. Individual carotenoids, measured in diet or blood, are reliable measures of intake of a variety of vegetables and fruits. In a nested case-control study of lung cancer in a cohort of Hawaiian Japanese men, individual carotenoids were measured in prediagnostic sera. Low serum levels of beta-cryptoxanthin, lycopene, and alpha-carotene, but not beta-carotene, were each modestly associated with elevated lung cancer risk (smoking-adjusted RRs = 1.3-1.5). There was no evidence of combined or synergistic effects for individual carotenoids. Thus, carotenoids, at physiologic levels, may not contribute substantially to lung cancer prevention. In the PLCO screening trial, we are investigating the relationship of vegetable and fruit intake, with quantity and variety assessed in several ways, to risk of colorectal adenoma. Greater intake of fruits and some vegetables, particularly deep yellow and dark green vegetables, is modestly, but significantly, associated with decreased risk for colorectal adenoma. Pyramid servings, a more comprehensive and quantitative approach to estimating food group intake, did not produce substantially different results than the more traditional number of servings/day.BREAST CANCER AND PROSTATE CANCER IN ASIAN-AMERICAN POPULATIONS International variation in breast cancer incidence and migrant studies indicate that modifiable factors play a major role in breast cancer etiology although the specific lifestyles and environmental exposures remain elusive. We designed a large, population-based case-control study of breast cancer in Asian-American women to take advantage of their diversity in lifestyle and breast cancer risk. Childhood, adolescent, and adult exposures were assessed by interviewing both study participants and their mothers. We observed a six-fold gradient in breast cancer incidence by migration patterns, comparable to the international differences in breast cancer incidence rates. Using the blood and urine samples that were collected, we initially focused on relationships, in the controls, between endogenous hormones and migration patterns. Estrogens did not differ significantly between Asian-American women born in Asia and the West. However, androgen levels were higher among Asian-Americans born in Asia. Thus, further efforts to understand the hormonal mechanisms underlying breast carcinogenesis should consider androgens as well as estrogens. The ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone, an indicator of estrogen metabolism pathways, was consistently lower (by 20%) in Asian-American women born in the West. The 2:16alpha ratio may reflect Asian lifestyles that influence estrogen metabolism and reduce breast cancer risk. We are now analyzing insulin-like growth factors (IGFs). Adiposity and weight gain in the decade preceding diagnosis, as well as height, were critical determinants of breast cancer risk in these Asian-American women. We are seeking biologic explanations, with emphasis initially on the IGFs.Childhood, adolescent, and adult soy intake were each independently associated with reduced risk of breast cancer. The strongest effect was seen for childhood soy intake, with a statistically significant 60% reduction in risk between extreme tertiles. Further analysis of the dietary and cultural pattern information collected will clarify whether soy seems uniquely protective or may only be serving as an indicator of other Asian lifestyles. Preliminary results suggest that the relative risk of breast cancer for a positive family history is similar in Asian-American women at different levels of Westernization. This constancy implies that the lifestyles responsible for lower risk among Asians may also modify genetically determined breast cancer risk.Foci of prostate cancer cells, like foci of breast cancer cells, seem to advance more rapidly in Western societies than in Asian societies. Elevated IGF-I has been postulated as a biomarker of more rapid progression, and possibly a cause. With prospectively stored serum samples from a cohort of Hawaiian Japanese men, we are exploring the relationship of IGF-I, IGFBP-3, free IGF-I, PSA, and proteomic patterns to risk of prostate cancer. Two important questions are whether IGF-I is equally predictive of indolent and aggressive prostate cancer and whether it is a true risk factor, preceding diagnosis by many years, or simply an early marker of preclinical disease.ENDOGENOUS HORMONE MEASUREMENT We have published a series of manuscripts on the reproducibility and utility of the commercial kits currently used to measure estrogens, estrogen metabolites, and androgens in blood and urine from premenopausal women, postmenopausal women, and men. While some of the assays are sufficiently reliable to discriminate among individuals, others are more problematic. In collaboration with Drs. Xia Xu and Timothy Veenstra at NCI-Frederick and Dr. Larry Keefer in the NCI Center for Cancer Research, we have developed a robust, relatively rapid liquid chromatography/mass spectroscopy procedure that can measure simultaneously 16 estrogens and estrogen metabolites in 0.5 ml of urine. A formal test of reproducibility, sensitivity, and specificity in a range of samples is being implemented. We anticipate that our approach can be extended to estrogen metabolite measurement in serum/plasma and tissue and that it can be modified to also measure androgens and phytoestrogens.NATIONAL HEALTH EPIDEMIOLOGIC FOLLOW-UP STUDY With prospective dietary data from the nationally representative U.S. Health Examination Epidemiological Follow-up Study, we used principal component analysis to explore the role of dietary patterns in the etiology of prostate cancer.

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。 同型半胱氨酸和各种叶酸形式和基因型的循环水平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通常吹捧为最有说服力的发现，可以从饮食和癌症的流行病学研究中出现，具有对肺和癌症的证据，对肺和癌症进行了强烈的证据。 在饮食或血液中测量的单个类胡萝卜素是多种蔬菜和水果摄入的可靠度量。 在夏威夷日本男性队列中肺癌的嵌套病例对照研究中，在诊断性血清中测量了单个类胡萝卜素。低血清β-晶氨酸，番茄红素和α-胡萝卜素（但不是β-胡萝卜素）的水平低与肺癌风险升高（吸烟调整后的RRS = 1.3-1.5）相关。没有证据表明对单个类胡萝卜素的联合或协同作用。因此，在生理水平上的类胡萝卜素可能不会对预防肺癌产生重大贡献。在PLCO筛查试验中，我们正在研究蔬菜和果实摄入量的关系，数量和多样性以多种方式评估为结直肠腺瘤的风险。 摄入水果和一些蔬菜，尤其是深黄色和深绿色蔬菜的摄入量是适度的，但显着，与结直肠腺瘤的风险降低有关。 金字塔份是一种估计食品群体摄入量的一种更全面和定量的方法，并没有产生与传统数量/天数量的结果大不相同的结果。在亚裔美国人人口中，乳腺癌的乳腺癌和前列腺癌在乳腺癌发病率和移民研究中的国际变化表明，可修改的因素在乳腺癌的eDeStyly和环境学上仍然具有主要作用。我们设计了一项基于人群的大型病例对照研究，对亚裔妇女的乳腺癌研究，以利用其在生活方式和乳腺癌风险方面的多样性。通过采访研究参与者及其母亲来评估童年，青少年和成人的暴露。 我们观察到通过迁移模式的乳腺癌发病率六倍，与乳腺癌发病率的国际差异相当。 使用收集的血液和尿液样品，我们最初专注于内源激素和迁移模式之间的关系。 在亚洲和西方出生的亚裔妇女之间的雌激素没有显着差异。但是，在亚洲出生的亚裔美国人中，雄激素水平较高。 因此，要了解乳腺癌作用的基础激素机制的进一步努力应考虑雄激素和雌激素。 在西方出生的亚裔美国妇女中，2-羟基链酮与16Alpha-Hydroxyestrone的比例（雌激素代谢途径的指标）始终较低（比20％）。 2：16Alpha比率可能反映了影响雌激素代谢并降低乳腺癌风险的亚洲生活方式。 我们现在正在分析胰岛素样生长因子（IGF）。 在诊断之前的十年中，肥胖和体重增加以及身高是这些亚裔妇女乳腺癌风险的关键决定因素。 我们正在寻求生物学解释，最初重点放在IGFS.儿童，青少年和成人大豆摄入量与乳腺癌风险降低之间的独立相关。 儿童大豆摄入量最大的作用是最大的，极端三物质之间的风险降低了60％。 对收集的饮食和文化模式信息的进一步分析将阐明大豆似乎是独特的保护性，还是只能作为其他亚洲生活方式的指标。 初步结果表明，在不同西化水平的亚裔妇女中，乳腺癌的相对风险相似。这种恒定性意味着，负责亚洲人风险较低的生活方式也可能会改变遗传确定的乳腺癌风险。前列腺癌细胞（如乳腺癌细胞的焦点）的范围似乎比亚洲社会在西方社会中迅速发展。升高的IGF-I被认为是更快进展的生物标志物，可能是原因。通过前瞻性存储的血清样品来自夏威夷日本男子的同类，我们正在探索IGF-I，IGFBP-3，游离IGF-I，PSA和蛋白质组学模式与前列腺癌风险的关系。两个重要的问题是，IGF-I是否同样可以预测酸味和侵略性的前列腺癌，以及它是否是真正的危险因素，在诊断之前多年，还是仅仅是临床前疾病的早期标记，我们已经在目前使用用于测量流过的商业习惯的依从性和尿液的启动性激素测量。绝经前妇女，绝经后妇女和男性。尽管某些测定法可以可靠地歧视个体，但其他测定法更为问题。 与Drs合作。 NCI-Frederick的Xu Xu和Timothy Veenstra和NCI癌症研究中心的Larry Keefer博士，我们开发了一种相对较快的液相色谱/质谱程序，可以同时测量0.5 mL尿液中的16个雌激素和雌激素代谢物。 正在实施一系列样本中的可重复性，灵敏度和特异性的正式测试。 We anticipate that our approach can be extended to estrogen metabolite measurement in serum/plasma and tissue and that it can be modified to also measure androgens and phytoestrogens.NATIONAL HEALTH EPIDEMIOLOGIC FOLLOW-UP STUDY With prospective dietary data from the nationally representative U.S. Health Examination Epidemiological Follow-up Study, we used principal component analysis to explore the role of dietary patterns in the etiology of prostate cancer.