Nutritional and Genetic Markers of Breast Cancer

乳腺癌的营养和遗传标志物

基本信息

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
项目类别：
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&apos 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

项目摘要

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¿以及它们的互动效果??女性患乳腺癌的风险健康研究 (WHS) 将确定并确认总共 1,100 例乳腺癌病例。我们将在 28,345 名已存档基线血液样本的参与者中检测五种营养成分。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）。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十二个相关候选基因的单倍型结构这些基因将包括谷氨酸- 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]、蛋氨酸合成酶还原酶 [MTRR]、丝氨酸羟甲基转移酶 [SHMT1]、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）。其中这些标志物可能与乳腺癌风险相关，首先是叶酸和维生素 B12 的影响。其次，叶酸和维生素。 B6和B12影响DNA的合成和修复第三，半胱氨酸是合成的关键氨基酸。谷胱甘肽（GSH），一种重要的细胞内抗氧化剂和解毒剂基因。编码半胱氨酸 GSH 生物合成的限速酶。叶酸与酒精摄入量相互作用会影响乳腺癌风险，但尚无已发表的数据。评估 GCLC、GCLM、RFC、MTR、MTRR、SHMT1 和 TYMS 多态性是否影响乳房这项研究的结果将有助于为公共卫生建议提供基础。关于叶酸和 B 族维生素摄入量的最佳水平，提出新的预防策略，并确定 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、储存血液样本的可用性、全面协变量信息和成本效率使该群体成为宝贵且特殊的资源乳腺癌的病因学调查。