Telomere length and chromosomal instability across various tissue types

描述（由申请人提供）：端粒长度（TL）在维持细胞增殖潜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端粒在生命过程中缩短是许多与年龄相关的健康状况的关键机制。在流行病学和临床研究中，经常观察到外周血细胞中端粒相对较短的个体患糖尿病的风险增加。 一系列疾病，包括心血管疾病、痴呆症和多种癌症。然而，这些关联很难解释，部分原因是不清楚如何解释。 外周血细胞中的TL反映了与疾病最相关的组织中的TL;没有研究以全面的方式解决这个问题。此外，目前还不清楚组织特异性TL是否实际上反映了在同一组织中测量的基因组不稳定性和DNA损伤水平。在这项提案中，我们的第一个目标是通过评估全血中测量的TL与从向基因型-组织表达（GTEx）项目捐赠组织的个体中获得的各种癌症易感组织（乳腺、结肠、食管、肾、肺、卵巢、胰腺、前列腺、皮肤、胃、睾丸和阴道）中测量的TL之间的相关性来解决这一知识缺口。每次比较将使用约100名个体。我们将使用高通量、基于探针的方法生成平均TL数据，该方法与传统的基于PCR的方法相比具有上级性能。我们的第二个目标是确定组织特异性TL是否是染色体不稳定性的指标。为了实现这一目标，我们将生成每种组织类型的体细胞拷贝数变异（CNV）和拷贝中性杂合性丢失（洛）事件的数据，并评估组织特异性TL与同一组织中体细胞CNV和洛事件丰度之间的关联，每次分析使用约100个个体。CNV和洛数据将使用来自高密度SNP阵列的探针强度数据和等位基因频率数据生成，所述高密度SNP阵列将针对来自每个组织的DNA样品运行。最后，使用已知影响白细胞TL和/或癌症风险的端粒维持基因位点的单核苷酸多态性（SNP）的现有数据，我们将寻找这些变体以组织特异性方式影响TL的证据。解决这些知识差距之间的相关性组织特异性TL，TL和染色体不稳定性之间的关系，和组织特异性的遗传效应TL是一个关键的一步，阐明的作用，TL在癌症和其他常见疾病的病因。我们的研究结果将为解释白细胞TL的流行病学研究结果提供基础，并有助于指导未来研究的设计，旨在阐明端粒长度与疾病之间的生物学机制和因果通路，长期目标是利用这些知识改善健康和预防疾病。

DESCRIPTION (provided by applicant): 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.