Cysteine, Related Gene Variants and Breast Cancer Risk

半胱氨酸、相关基因变异和乳腺癌风险

• 批准号: 7666316
• 负责人: Walter C. Willett
• 金额: $ 32.53万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666316
• 关键词: Acetylcysteine; Amino Acids; Anabolism; Antioxidants; Arts; Blood; Blood specimen; Breast; Candidate Disease Gene; Catabolism; Catalytic Domain; Cells; Collection; Cysteine; Cysteine Metabolism Pathway; Data; Development; Documentation; Enzymes; Etiology; Funding; Future; GCLC gene; GCLM gene; Generations; Genes; Genetic; Genetic Markers; Genetic Variation; Genotype; Glutamate-Cysteine Ligase; Glutathione; Haplotypes; International; Investigation; Life Style; Malignant Neoplasms; Medical; Membrane; National Cancer Institute; Nurses' Health Study; Nutritional; Oxidative Stress; Participant; Plasma; Population Study; Prospective Studies; Public Health; Publishing; Reactive Oxygen Species; Research Personnel; Risk; Role; SNP genotyping; Source; Statistical Methods; Structure; Variant; Woman; cancer chemoprevention; cancer risk; carcinogenesis; cohort; cost; cysteinylglycine; dietary supplements; extracellular; follow-up; genotyping technology; glutathione synthase; improved; malignant breast neoplasm; novel; oxidative damage; prevent; programs; prospective

DESCRIPTION (provided by applicant): Cysteine is the rate-limiting amino acid in biosynthesis of glutathione (GSH)-the key intracellular antioxidant and detoxifying agent. Limited data have suggested that high circulating levels of cysteine may prevent the development of breast cancer. Cysteinylglycine, a product of the extracellular GSH catabolism by y-glutamyltranspeptidase (GGT1), is involved in the generation of reactive oxygen species. However, no study has assessed the relation of Cysteinylglycine levels to breast cancer risk. Although genetic differences in GSH biosynthesis from cysteine and GSH catabolism could influence breast cancer risk and may modify the effect of cysteine and Cysteinylglycine on risk of breast cancer, no published data are available. We thus propose to conduct a prospective study of plasma cysteine, Cysteinylglycine, gene variants involved in GSH biosynthesis from cysteine and GSH catabolism, and their interactive effects on risk of breast cancer in two large prospective cohorts, the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII). Applying state-of-the-art genotyping technology and statistical methods, we will evaluate common functional variants and determine the structure of haplotypes in four relevant candidate genes, including glutamate-cysteine ligase (as known as y-glutamylcysteine synthetase, a rate-limiting enzyme catalyzing the first step of GSH biosynthesis from cysteine with two subunits [GCLC, catalytic subunit; GCLM, regulatory subunitj), glutathione synthetase (GSS, an enzyme catalyzing the second step of GSH biosynthesis) and GGT1 (an enzyme involved in the GSH catabolism to generate Cysteinylglycine and in the transport of cysteine into the cell). Associations with these candidate genes would provide mechanistic evidence for the association between plasma cysteine and Cysteinylglycine and breast cancer risk. A total of 2279 incident breast cancer cases and their matched controls will be identified in the NHS and NHSII cohorts among women with achieved blood samples and free of cancer at baseline. The NHS and NHSII cohorts have a large number of confirmed cases of breast cancer, long duration, high follow-up rates, and comprehensive covariate information, thus providing an extraordinary opportunity to examine the main effects of cysteine-related gene variants, plasma cysteine and Cysteinylglycine, and their interactions in relation to breast cancer risk. We will explore interactions among these candidate genes as well. Findings from this proposed study will help elucidate the role of cysteine in breast carcinogenesis, and may suggest future approaches for breast cancer chemoprevention, as /V-acetylcysteine and cysteine dietary supplements can readily improve cysteine status.

描述（由申请人提供）：半胱氨酸是谷胱甘肽（GSH）生物合成中的速率氨基酸 - 关键的细胞内抗氧化剂和排毒剂。有限的数据表明，高循环水平的半胱氨酸可能会阻止乳腺癌的发展。 Cysteinylglycine是Y-谷氨基肽酶（GGT1）的细胞外GSH分解代谢的产物，参与了活性氧的产生。但是，尚无研究评估半胱氨酸甘氨酸水平与乳腺癌风险的关系。尽管半胱氨酸和GSH分解代谢的GSH生物合成的遗传差异可能会影响乳腺癌的风险，并可能改变半胱氨酸和半胱氨酸甘氨酸对乳腺癌风险的影响，但没有公开的数据可用。因此，我们建议对血浆半胱氨酸，cysteinylglycine，与GSH生物合成的基因变体进行前瞻性研究，以及来自半胱氨酸和GSH分解代谢的GSH生物合成及其对两个大型前瞻性队列中乳腺癌风险的互动影响，护士健康研究（NHS）以及护士健康研究II（NHS）II（NHS）II（NHSSII）。 Applying state-of-the-art genotyping technology and statistical methods, we will evaluate common functional variants and determine the structure of haplotypes in four relevant candidate genes, including glutamate-cysteine ligase (as known as y-glutamylcysteine synthetase, a rate-limiting enzyme catalyzing the first step of GSH biosynthesis from cysteine with two subunits [GCLC，催化亚基，GCLM，调节子量），谷胱甘肽合成酶（GSS，一种酶，催化GSH生物合成的第二步）和GGT1（酶（一种酶）与这些候选基因的关联将为血浆半胱氨酸和半胱氨酸甘氨酸与乳腺癌风险之间的关联提供机械证据。在NHS和NHSII队列中，将确定2279例乳腺癌病例及其匹配的对照组，这些妇女的血液样本已达到血液样本，并且在基线时没有癌症。 NHS和NHSII队列有大量确认的乳腺癌病例，长期持续时间，高后续率和全面的协变量信息，因此提供了一个非凡的机会，可以检查与半胱氨酸相关的基因变体的主要影响，血浆半胱氨酸半胱氨酸和甲基糖甘氨酸甘氨酸的相互作用以及其在乳腺癌中的相互作用。我们还将探索这些候选基因之间的相互作用。这项拟议的研究的结果将有助于阐明半胱氨酸在乳腺癌发生中的作用，并可能建议对乳腺癌化学预防的未来方法，AS /V-乙酰半胱氨酸和半胱氨酸饮食补充剂可以轻松改善半胱氨酸状态。