Telomere length and chromosomal instability across various tissue types

项目摘要/摘要 端粒长度(TL)在维持细胞增殖能力和基因组稳定性方面起着核心作用。 导致许多研究人员假设，在生命过程中端粒缩短是一种关键机制 许多与年龄相关的健康状况的潜在原因。在流行病学和临床研究中，患有 外周血细胞中相对较短的端粒经常被观察到有更大的风险。 疾病，包括心血管疾病、痴呆症和多种癌症。然而，这些 相关性很难解释，部分原因是不清楚外周血细胞中的TL反映得有多好 TL在与疾病最相关的组织中；没有研究以全面的方式解决这一问题。 此外，目前还不清楚组织特异性TL是否真的反映了基因组不稳定和DNA损伤的水平 在相同的组织中测量。在这项建议中，我们的首要目标是通过评估 全血TL测定值与不同肿瘤易感组织(乳腺、 结肠、食道、肾脏、肺、卵巢、胰腺、前列腺、皮肤、胃、睾丸和阴道) 向GTEx项目捐赠组织的个人。大约100 每一次比较都将使用个人。我们将使用高吞吐量生成平均TL数据， 与传统的基于PCR的方法相比，基于探针的方法具有更好的性能。我们的第二个 目的是确定组织特异性TL是否是染色体不稳定的指标。为了实现这一目标，我们将 生成有关体细胞拷贝数变异(CNV)和拷贝中性杂合性丢失(LOH)事件的数据 对于每种组织类型，评估组织特异性TL与体细胞CNV丰度之间的关联 在相同的组织中发生LOH事件，每次分析使用大约100个人。CNV和LOH 将使用来自高密度SNP的探针强度数据和等位基因频率数据来生成数据 将对每个组织的DNA样本进行检测的阵列。最后，使用关于单核苷酸的现有数据 端粒维持基因座上已知的影响白细胞TL和/或癌症风险的SNPs，我们 将寻找这些变异以组织特有的方式影响TL的证据。解决这些问题 关于组织特异性TL之间的相关性、TL和TL之间的关系的知识差距 染色体不稳定性和组织特异性遗传效应对TL的影响是阐明其作用的关键一步 在癌症和其他常见疾病的病因学中。我们的结果将为下一步的 解释白细胞TL的流行病学研究结果，并帮助指导未来的设计 研究旨在阐明端粒长度和端粒长度之间的生物学机制和致病途径。 其长期目标是利用这一知识改善健康和预防疾病。

PROJECT SUMMARY/ABSTRACT Telomere length (TL) plays a central role in maintaining cellular proliferative potential and genome stability, leading many investigators to hypothesize that telomere shortening over the life course is a critical mechanism underlying many age-related health conditions. In epidemiological and clinical studies, individuals with relatively short telomeres in peripheral blood cells are often observed to be at increased risk for a wide array of diseases, including cardiovascular conditions, dementia, and multiple types of cancer. However, these associations are difficult to interpret, in part because it is not clear how well TL in peripheral blood cells reflects TL in the tissues most relevant to disease; no studies have addressed this issue in a comprehensive fashion. Furthermore, it is unclear if tissue-specific TL actually reflects levels of genomic instability and DNA damage measured in the same tissue. In this proposal, our first aim is to address this knowledge gap by assessing the correlation between TL measured in whole blood and TL measured in various cancer-prone tissues (breast, colon, esophagus, kidney, lung, ovary, pancreas, prostate, skin, stomach, testis, and vagina) obtained from individuals who have donated tissues to the Genotype-Tissue Expression (GTEx) project. Approximately 100 individuals will be used for each comparison. We will generate data on average TL using a high-throughput, probe-based method that has superior performance compared to traditional PCR-based methods. Our second aim is to determine if tissue-specific TL is an indicator for chromosomal instability. To achieve this aim, we will generate data on somatic copy number variation (CNV) and copy-neutral loss of heterozygosity (LOH) events for each tissue type and assess the association between tissue-specific TL and abundance of somatic CNV and LOH events in the same tissue, using approximately 100 individuals for each analysis. CNV and LOH data will be generated using both probe intensity data and allele frequency data derived from high-density SNP arrays that will be run for DNA samples from each tissue. Finally, using existing data on single nucleotide polymorphisms (SNPs) at telomere maintenance gene loci known to effect leukocyte TL and/or cancer risk, we will search for evidence that these variants influence TL in a tissue-specific fashion. Addressing these knowledge gaps regarding correlations among tissue-specific TLs, the relationship between TL and chromosomal instability, and tissue-specific genetic effects on TL is a critical step towards elucidating the role of TL in the etiology of cancer and other common diseases. Our results will provide a foundation for the interpretation of findings from epidemiological studies of leukocyte TL and help guide the design of future studies aimed at elucidating the biological mechanisms and causal pathways linking telomere length and disease, with the long-term goal of using this knowledge to improving health and prevent disease.