Telomere dysfunction, oxidative damage and breast cancer risk

端粒功能障碍、氧化损伤和乳腺癌风险

• 批准号: 7213985
• 负责人: Jing Shen
• 金额: $ 8.76万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7213985
• 关键词: breast neoplasms; cancer risk; clinical research; telomere

DESCRIPTION (provided by applicant): Telomeres are specialized DNA-protein structures at the ends of linear chromosomes, and are essential for maintaining the integrity and stability of the genome. Telomere dysfunction can lead to genomic instability that in turn drives the tumorigenic process in pre-malignant breast lesions and normal breast tissues. Several genetic or environmental factors may affect telomere dysfunction, and modify breast cancer risk: (1) progressive loss of telomere repeat sequences due to the problem of replicating chromosome ends; (2) oxidative damage to telomeric DNA accelerating telomere shortening; (3) disruption of higher-order telomere structures due to defects in various telomere-binding proteins; (4) age, cigarette smoking, chronic inflammation and epigenetic modifications, etc. But there is little evidence from population studies. The broad and long-term objectives of the study are to clarify the etiological role of telomere dysfunction in breast cancer risk and the potential determinants for shortened telomeres. The specific aims of the present study are to: (1) Explore the association between telomere dysfunction and breast cancer risk in a large population-based case-control study - the Long Island Breast Cancer Study Project (LIBCSP). (2) Evaluate the modifying effects of oxidative damage (urinary 15-F2t-lsoP and 8-oxodG levels as biomarkers) and antioxidant capacity (antioxidants intake levels obtained from FFQ) on telomere dysfunction for breast cancer risk. (3) Screen for SNPs in key telomere stability genes that potential affect telomere function. Associations between 96 SNPs and shortening telomere, breast cancer risk will be determined. Quantitative PCR (Q-PCR) will be used to measure telomere length in peripheral blood lymphocytes (PBLs) among 800 cases and 800 controls as a biomarker of telomere dysfunction; Urinary 15-F2t-lsoP levels will be analyzed using immunoassay kits. Urinary 8-oxodG levels will be analyzed by competitive ELISA. The high through-put SNPIexTM genotyping system will be used to genotyped potential functional SNPs in key telomere stability genes. Understanding the role of telomere dysfunction in breast cancer risk and the modifying effect of oxidative damage and antioxidant capacity has important implications for improved preventive, diagnostic and treatment strategies for breast cancer.

描述（由申请人提供）：端粒是线性染色体末端的专门DNA-蛋白结构，对于维持基因组的完整性和稳定性至关重要。端粒功能障碍会导致基因组不稳定性，从而驱动了恶性乳房病变和正常乳腺组织中的致瘤过程。几个遗传或环境因素可能会影响端粒功能障碍，并改变乳腺癌的风险：（1）由于复制染色体末端的问题，端粒重复序列的逐渐丧失； （2）对端粒DNA加速端粒缩短的氧化损伤； （3）由于各种端粒结合蛋白缺陷而导致的高阶端粒结构的破坏； （4）年龄，吸烟，慢性炎症和表观遗传修饰等，但人口研究的证据很少。该研究的广泛和长期目标是阐明端粒功能障碍在乳腺癌风险中的病因和缩短端粒缩短的决定因素。本研究的具体目的是：（1）在一项基于人群的大型病例对照研究中，探索端粒功能障碍与乳腺癌风险之间的关联 - 长岛乳腺癌研究项目（LIBCSP）。 （2）评估氧化损伤（尿15-F2T-LSOP和8-OXODG水平作为生物标志物）和抗氧化剂能力（从FFQ获得的抗氧化剂摄入水平）对乳腺癌风险风险的氧化作用（从FFQ获得的抗氧化剂摄入水平）。 （3）潜在影响端粒功能的关键端粒稳定性基因中SNP的屏幕。将确定96个SNP和缩短端粒的关联，乳腺癌风险。定量PCR（Q-PCR）将用于测量800例外周血淋巴细胞（PBL）中的端粒长度和800例对照，作为端粒功能障碍的生物标志物；尿15-F2T-LSOP水平将使用免疫测定试剂盒进行分析。竞争性ELISA将分析尿液8-OXODG水平。高渗透SNPIEXTM基因分型系统将用于基因分型在关键端粒稳定基因中的潜在功能SNP。了解端粒功能障碍在乳腺癌风险中的作用以及氧化损伤和抗氧化能力的修改作用对改善乳腺癌的预防，诊断和治疗策略具有重要意义。