Cohort Study of Genetic Susceptibility to Breast Cancer

描述（由申请人提供）：我们建议继续研究女性乳腺癌的环境和遗传决定因素。在外周血白色细胞中测量的端粒长度已经成为衰老和癌症风险的生物标志物。端粒是染色体末端的TTAGGG重复复合物，可以防止染色体的降解、融合和异常重组。由于端粒随着每个细胞复制周期而缩短，因此它们是细胞所经历的细胞分裂次数的指标。较短的端粒长度与头颈癌、肺癌、肾细胞癌和膀胱癌的风险有关，然而，没有关于乳腺癌的研究发表，尽管端粒长度已被证明在老年妇女的正常乳腺组织中缩短。双胞胎研究表明，端粒长度有很大的遗传成分，然而，没有遗传变异与端粒长度。我们建议（i）确定外周白色血细胞中端粒长度是否是来自护士健康研究I和II的绝经前和绝经后乳腺癌以及来自妇女健康研究的绝经后妇女的乳腺癌风险的预测因子;（二）使用多阶段设计，从NHS I的2400名绝经后妇女中完成全基因组SNP扫描开始，以定位遗传性遗传变异与端粒缩短率相关;（iii）检查端粒长度的环境和生活方式预测因素。该项目的新颖之处在于，它将是第一个将来自全基因组SNP扫描的密集数据应用于连续定量结果的项目之一。该项目将首次整合端粒长度的遗传和环境决定因素，并将深入了解与年龄相关的癌症的生物学和可改变的原因。端粒是重复的核苷酸序列，它保护我们染色体的末端不被降解。它们在细胞的生命过程中会缩短，因此代表了衰老的标志。我们将研究白色血细胞中较短的端粒是否是女性患乳腺癌风险的标志，并寻求较短端粒的遗传和生活方式决定因素。了解与年龄相关的端粒缩短的原因可能会提供降低乳腺癌风险的可修改方法。

DESCRIPTION (provided by applicant): We propose to continue our study of the environmental and inherited determinants of breast cancer in women. Telomere length, measured in peripheral blood white cells, has emerged as a biomarker of ageing, and cancer risk. Telomeres are TTAGGG repeat complexes at the end of chromosomes, that protect against degradation, fusion, and aberrant recombination of chromosomes. As telomeres shorten with each cell replication cycle, they are an indicator of the number of cell divisions a cell has undergone. Shorter telomere length has been associated with risks of head and neck, lung, renal cell and bladder cancers, however, no studies of breast cancer have been published, although telomere length has been shown to shorten in normal breast tissue in older women. Twin studies have shown that telomere length has a substantial heritable component, however, no genetic variants have been linked to telomere length. We propose to (i) Establish whether telomere length in peripheral white blood cells is a predictor of breast cancer risk in premenopausal and postmenopausal breast cancer from the Nurses' Health Studies I and II, and postmenopausal women from the Women's Health Study; (ii) use a multistage design starting with a completed whole genome SNP scan among 2400 postmenopausal women in NHS I to locate the inherited genetic variants associated with rate of telomere shortening; and (iii) examine the environmental and lifestyle predictors of telomere length. Among the novel aspects of this project is that it will be one of the first to apply dense data from a whole genome SNP scan to a continuous quantitative outcome. This project will integrate the genetic and environmental determinants of telomere length for the first time, and should give insight into the biological and modifiable causes of age-related cancers. Telomeres are repeated nucleotide sequences that protect the ends of our chromosomes from degradation. They get shortened during a cell's life and thus represent a marker of aging. We will examine whether shorter telomeres in white blood cells are a marker of a woman's risk of breast cancer, and seek the genetic and lifestyle determinants of shorter telomeres. Understanding the causes of the age-related shortening of telomeres may offer modifiable means of reducing breast cancer risk.