Nutritional and Genetic Markers of Breast Cancer

乳腺癌的营养和遗传标志物

• 批准号: 7463655
• 负责人: SHUMIN ZHANG
• 金额: $ 28.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463655
• 关键词: 14q32.3; 17p11.2; 18p11.32; 19q13.2; 1p22; 1p36.3; 1q43; 21q22.3; 22q11.21; 6p12; 7q36.1; Affect; Alcohol consumption; Alcohols; Amino Acids; Anabolism; Antioxidants; Archives; Arts; Aspirin; Base Excision Repairs; Biological Assay; Biological Markers; Blood; Blood specimen; Candidate Disease Gene; Carbon; Cardiovascular Diseases; Case-Control Studies; Catalytic Domain; Catechol Estrogens; Catechol O-Methyltransferase; Class; Collection; Complement; Complement component C1; Cysteine; DNA; DNA Double Strand Break; DNA Methylation; DNA Repair; DNA Repair Gene; DNA biosynthesis; DNA chemical synthesis; Data; Development; Documentation; Enzymes; Etiology; Excision Repair; Folate; Folch-Pi apoprotein; Folic Acid Deficiency; Funding; GAG Gene; GCLC gene; GCLM gene; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Glutamate-Cysteine Ligase; Glutathione; Glycine Hydroxymethyltransferase; Haplotypes; Heart; Homocysteine; Homocystine; Individual; Institutes; Intake; Investigation; Length; Life Style; Lung; MTHFR gene; Malignant Neoplasms; Medical; Metabolism; Methionine; Methylation; Methylenetetrahydrofolate reductase (NADPH); Methyltransferase Gene; Myelin Proteolipid Protein; National Cancer Institute; Numbers; Nutrient; Nutritional; Participant; Pathway interactions; Plasma; Prevention strategy; Primary Prevention; Prospective Studies; Public Health; Publishing; Pyridoxal Phosphate; Rate; Recommendation; Research Personnel; Resources; Risk; Roentgen Rays; Role; SLC19A1 gene; Sample Size; Statistical Methods; Structure; Supplementation; TYMS gene; Tandem Repeat Sequences; Thymidylate Synthase; Untranslated Regions; Variant; Vitamin B 12; Vitamin B Complex; Vitamin B6; Vitamin E; Vitamins; Woman; Women' s Health; XRCC1 gene; XRCC2 gene; XRCC3 gene; base; cancer risk; chromosome 5q loss; cohort; cost; design; follow-up; genotyping technology; homologous recombination; malignant breast neoplasm; methionine synthase reductase; methyl group; novel; nutrient blood level; prevent; programs; prospective; recombinational repair; repaired

We propose to conduct a prospective study of nutritional biomarkers and corresponding gene variants involved in one-carbon metabolism¿and their interactive effects¿on breast cancer risk in the Women's Health Study (WHS). A total of 1,100 incident cases of breast cancer will be identified and confirmed among 28,345 participants with archived baseline blood specimens. We will assay five nutritional biomarkers (i.e. plasma folate, vitamins B6 and B12, cysteine, and homocysteine). Applying state-of-the- art genotyping technology and statistical methods, we will evaluate functional variants and determine the structure ofhaplotypes in twelve relevant candidate genes. These genes will include glutamate- cysteine ligase (GCLC [catalytic subunit] and GCLM[regulatory subunif]), folate-metabolizing genes (reducedfolate carrier-1[RFC], 5,10-methylene-tetrahydrofolate reductase [MTHFR], methionine synthase [MTR], methionine synthase reductase [MTRR], serine hydroxymethyltransferase [SHMT1], and thymidylate synthase [TYMS]), catechol-O-methyltransferase (COMT), and DNA repair genes (X- ray repair cross complementing [XRCC]-1, 2, and 3). There are at least three interrelated pathways by which these markers may be associated with breast cancer risk. First, folate and vitamin B12 affect methyl group availability and may thus prevent abnormal DNA methylation. Second, folate and vitamins B6 and B12 influence DNA synthesis and repair. Third, cysteine is the key amino acid in the synthesis of glutathione (GSH), an important intracellular antioxidant and detoxifying agent. GCLC and GCLM genes encode a rate-limiting enzyme for GSH biosynthesis from cysteine. Available data also suggest that folate interacts with alcohol intake to affect breast cancer risk. However, no published data have evaluated whether GCLC, GCLM, RFC, MTR, MTRR, SHMT1, and TYMS polymorphisms affect breast cancer risk. Findings from this study will help provide a basis for public health recommendations regarding optimal levels of folate and B vitamin intakes, suggest new prevention strategies, and identify high-risk individuals. Several unique features of the WHS, including its prospective design, large sample size, long duration, high follow-up rates, availability of stored blood specimens, comprehensive covariate information, and cost efficiency, make this cohort a valuable and exceptional resource for the etiologic investigation of breast cancer.

我们建议对营养生物标志物和相应的基因变异进行前瞻性研究 参与一碳代谢及其对女性乳腺癌风险的相互作用 健康研究（WHS）。将确定和确认总共1，100例乳腺癌病例 在28，345名具有存档基线血液样本的参与者中。我们将分析五种营养成分， 生物标志物（即血浆叶酸、维生素B6和B12、半胱氨酸和同型半胱氨酸）。应用国家的- 艺术基因分型技术和统计方法，我们将评估功能变异，并确定 12个相关候选基因的单倍型结构。这些基因包括谷氨酸- 半胱氨酸连接酶（GCLC [催化亚基]和GCLM[调节亚基]），叶酸代谢基因 （还原叶酸载体-1 [RFC]，5，10-亚甲基-四氢叶酸还原酶[MTHFR]，蛋氨酸 合成酶[MTR]，甲硫氨酸合成酶还原酶[MTRR]，丝氨酸羟甲基转移酶[SHMT 1]， 和胸苷酸合成酶[TYMS]）、儿茶酚-O-甲基转移酶（COMT）和DNA修复基因（X- 射线修复交叉互补[XRCC]-1，2和3）。至少有三种相互关联的途径， 这些标志物可能与乳腺癌风险有关。首先，叶酸和维生素B12影响 甲基基团的可用性，从而可以防止异常的DNA甲基化。二、叶酸和维生素 B6和B12影响DNA的合成和修复。第三，半胱氨酸是合成 谷胱甘肽（GSH），一种重要的细胞内抗氧化剂和解毒剂。GCLC和GCLM基因 编码半胱氨酸生物合成GSH的限速酶。现有数据还表明， 叶酸与酒精摄入相互作用，影响乳腺癌风险。然而，没有公布的数据 评估GCLC、GCLM、RFC、MTR、MTRR、SHMT 1和TYMS多态性是否影响乳腺癌 癌症风险。这项研究的结果将有助于为公共卫生建议提供依据 关于叶酸和B族维生素摄入的最佳水平，提出新的预防策略，并确定 高危人群。WHS的几个独特之处，包括其前瞻性设计，大样本 规模大，持续时间长，随访率高，储存血液标本的可用性，全面 协变量信息和成本效率，使这一群体成为有价值的和特殊的资源， 乳腺癌的病因学调查。