Nutrition, Metabolism, and Cancer

叶酸和单碳代谢叶酸是一碳（甲基）代谢所必需的，这是一种涉及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种酶的最佳活性。在一项基于社区的浸润性宫颈癌病例对照研究中，我们发现血清同型半胱氨酸水平高与发病风险增加100-200%相关，而血清或红细胞叶酸水平低与发病风险仅增加20-60%相关。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，或者是单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种常见多态性和蛋氨酸合成酶基因的一种常见多态性的变体形式都与宫颈癌风险升高有关。风险通常随着变异基因拷贝数的增加而增加。这些结果表明，单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。目前正在分析通路基因的其他多态性。我们还在前列腺癌、肺癌、结直肠癌和卵巢癌（PLCO）队列中探索单碳代谢在结直肠癌和乳腺癌病因学中的作用。大量晚期结直肠腺瘤（1200例）的鉴定将使我们能够系统地搜索关键单碳代谢基因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。我们还将探讨血液中同型半胱氨酸水平与各种叶酸形态和基因型之间的关系。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饮食和癌症的流行病学研究中最有说服力的发现，其中最有力的证据是肺癌和结直肠癌。在饮食或血液中测量的单个类胡萝卜素是衡量各种蔬菜和水果摄入量的可靠指标。在一组夏威夷日本男性肺癌的巢式病例对照研究中，在诊断前血清中测量了个体类胡萝卜素。血清中β -隐黄质、番茄红素和α -胡萝卜素（而非β -胡萝卜素）的低水平均与肺癌风险升高有一定的相关性（吸烟调整后的相对危险度= 1.3-1.5）。没有证据表明单个类胡萝卜素有联合或协同作用。因此，在生理水平上，类胡萝卜素可能对预防肺癌没有实质性的作用。在PLCO筛选试验中，我们正在调查蔬菜和水果摄入量与结直肠腺瘤风险的关系，并以几种方式评估其数量和种类。多吃水果和一些蔬菜，特别是深黄色和深绿色蔬菜，与降低结直肠腺瘤的风险有轻微但显著的联系。金字塔份量，一种更全面和定量的方法来估计食物组的摄入量，与更传统的每日份量并没有产生实质性的不同结果。乳腺癌发病率的国际差异和移民研究表明，可改变的因素在乳腺癌病因中起主要作用，尽管具体的生活方式和环境暴露仍然难以捉摸。我们设计了一项基于人群的亚裔美国女性乳腺癌病例对照研究，以利用她们生活方式的多样性和乳腺癌风险。通过采访研究参与者及其母亲来评估儿童、青少年和成人的暴露程度。我们观察到乳腺癌发病率在迁移模式上有6倍的梯度，与乳腺癌发病率的国际差异相当。利用收集到的血液和尿液样本，我们最初关注的是内源性激素和迁移模式之间的关系。在亚洲和西方出生的亚裔美国女性的雌激素水平没有显著差异。然而，在亚洲出生的亚裔美国人的雄激素水平更高。因此，进一步了解乳腺癌发生的激素机制应该考虑雄激素和雌激素。在西方出生的亚裔美国女性中，2-羟孕酮与16 -羟孕酮（雌激素代谢途径的指标）的比例一直较低（低20%）。2:16的比例可能反映了亚洲人的生活方式，这种生活方式会影响雌激素代谢，降低患乳腺癌的风险。我们现在正在分析胰岛素样生长因子（igf）。在这些亚裔美国女性中，诊断前10年的肥胖和体重增加以及身高是乳腺癌风险的关键决定因素。我们正在寻找生物学上的解释，最初的重点是igf。儿童、青少年和成人大豆摄入量分别与降低乳腺癌风险相关。对儿童大豆摄入量的影响最大，从统计上看，极端摄入量之间的风险降低了60%。对所收集的饮食和文化模式信息的进一步分析将阐明大豆是否具有独特的保护作用，或者可能只是作为其他亚洲生活方式的一个指标。初步结果表明，在不同程度的西化程度的亚裔美国女性中，阳性家族史患乳腺癌的相对风险相似。这种稳定性意味着亚洲人的低风险生活方式也可能改变基因决定的乳腺癌风险。前列腺癌细胞的病灶，就像乳腺癌细胞的病灶一样，在西方社会似乎比在亚洲社会发展得更快。升高的igf - 1被认为是更快进展的生物标志物，也可能是病因。通过前瞻性储存的夏威夷日本男性血清样本，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 - 1是否同样能预测惰性前列腺癌和侵袭性前列腺癌，以及它是一个真正的危险因素，在诊断前多年，还是仅仅是临床前疾病的早期标志。内源性激素测量我们已经发表了一系列关于目前用于测量绝经前妇女、绝经后妇女和男性血液和尿液中的雌激素、雌激素代谢物和雄激素的商业试剂盒的可重复性和实用性的手稿。虽然有些检测方法足够可靠，可以区分个体，但其他检测方法则存在更多问题。在与博士合作。NCI- frederick的Xia Xu和Timothy Veenstra以及NCI癌症研究中心的Larry Keefer博士，我们开发了一种强大的，相对快速的液相色谱/质谱方法，可以同时测量0.5 ml尿液中的16种雌激素和雌激素代谢物。正在对一系列样品的重现性、敏感性和特异性进行正式测试。我们期望我们的方法可以扩展到血清/血浆和组织中雌激素代谢物的测量，并且它可以被修改为也可以测量雄激素和植物雌激素。研究人员利用具有全国代表性的美国健康检查流行病学随访研究的前瞻性饮食数据，采用主成分分析来探讨饮食模式在前列腺癌病因学中的作用。

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.