Telomere dysfunction, oxidative damage and breast cancer risk

描述(申请人提供)：端粒是位于线性染色体末端的特殊DNA-蛋白质结构，对维持基因组的完整性和稳定性是必不可少的。端粒功能障碍可导致基因组不稳定，进而推动癌前病变和正常乳腺组织的肿瘤形成过程。一些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)由于染色体末端复制问题而导致的端粒重复序列的进行性丢失；(2)端粒DNA的氧化损伤加速端粒缩短；(3)由于各种端粒结合蛋白的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。这项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学作用以及端粒缩短的潜在决定因素。本研究的具体目的是：(1)在一个以人群为基础的大型病例对照研究--长岛乳腺癌研究项目(LIBCSP)中，探索端粒功能障碍与乳腺癌风险之间的关系。(2)评价氧化损伤(尿15-F2T-lsoP和8-oxodG水平作为生物标志物)和抗氧化能力(从FFQ获得的抗氧化剂摄入量水平)对乳腺癌风险的端粒功能障碍的调节作用。(3)筛选可能影响端粒功能的关键端粒稳定基因中的SNPs。96个SNP与端粒缩短和乳腺癌风险的相关性将被确定。采用定量聚合酶链式反应(Q-PCR)检测800例患者和800例对照组外周血淋巴细胞(PBL)端粒长度，用免疫试剂盒检测尿15-F2T-lsoP水平。尿8-oxodG水平将采用竞争性酶联免疫吸附试验进行分析。高通量的SNPIexTM基因分型系统将用于关键端粒稳定基因的潜在功能SNPs的基因分型。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调节作用对于改进乳腺癌的预防、诊断和治疗策略具有重要意义。

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.