Genetic Epidemiology of Telomere Maintenance and Cancer Etiology

端粒由长的TTAGGG核苷酸重复序列和染色体末端的相关蛋白质组成，对维持染色体的完整性是必不可少的。为了保护染色体末端，端粒酶逆转录酶(TERT)及其RNA组分(TERC)和由六种蛋白质(基因名称：TERF1、TERF2、TINF2、TERF2IP、ACD和POT1)组成的有序蛋白质复合体Shelterin保护端粒不发生端到端的融合。端粒重复序列随着细胞的每次分裂而丢失，部分原因是染色体3“端的不完全复制。端粒磨损最终导致端粒过短，导致细胞衰老或细胞危机，包括细胞凋亡、基因组不稳定或细胞寿命缩短。1)先天性角化不良(DC)研究：DC是一种遗传性骨髓衰竭综合征(IBMFS)和癌症易感性疾病，以端粒生物学异常为特征，由端粒通路中几个基因之一的胚系突变引起。我们最近发现，用流式细胞仪-FISH测量的端粒长度是区分DC和其他IBMFS的敏感和特异的指标。这项研究的主要目标之一是寻找新的基因，这些基因可能解释了目前60%的DC患者在DKC1、TERC或TERT上没有可检测到的突变。我们最近完成了一项连锁研究，发现TINF2在几个DC家系中发生了突变。这项研究还侧重于仔细的临床表型。一项关于DC畸形的全面研究也在进行中。这些研究将提供更多关于基因-表型相互作用的具体数据，并有助于DC的诊断。2)靶组织中的端粒长度：这是一组小型的方法学研究，旨在阐明端粒长度在个体内的差异，最终目的是改善对不同细胞类型和端粒长度测定方法的可比性的理解。流行病学研究通常使用从血液或口腔细胞中提取的DNA，但尚未发表对血液和口腔细胞DNA端粒长度的直接比较。这项研究将评估参与遗传性骨髓衰竭综合征研究的受试者血液、口腔细胞和成纤维细胞DNA中端粒长度的个体内和个体间差异。它还将研究卵巢癌研究中健康对照组口腔细胞和血液DNA之间的端粒长度差异。3)端粒长度是前列腺癌的危险因素：端粒、端粒缩短和端粒酶活性已成为前列腺癌发生的重要因素。人类前列腺癌发生的最早阶段可能是由于端粒变短、功能失调而导致染色体不稳定的结果。这是PLCO队列中前列腺癌病例对照研究的一部分。对1200名对照组和700名晚期前列腺癌患者进行了端粒长度测定，未发现端粒长度与前列腺癌风险之间的明显关联。然而，较长的端粒与更健康的生活方式有关。4)端粒长度的新遗传决定因素：3中描述的相同对象也是全基因组关联研究的一部分(CGEMS，癌症遗传易感性标记)。通过与哈佛大学公共卫生学院的Immaculata DeVivo博士和David Hunter博士的合作，我们将增加来自护士S健康研究的1200名健康对照，他们是CGEMS乳腺癌全基因组扫描的一部分。我们正在评估在CGEMS GWAS的同一平台上测量的基因变异与端粒长度(两者都在同一实验室测量)之间的关系，在健康对照组中：1200名男性和1200名女性。最后，在前列腺癌病例和对照组中，将评估影响端粒长度的基因类型之间的相互作用。。5)端粒基因的群体遗传学：我们之前已经证明，在端粒生物学中重要的基因中，核苷酸多样性很低。这项研究将通过评估来自世界各地的1000个人的30多个端粒生物基因的遗传变异来跟进这些发现。在病例对照研究中，对人群历史和用于基因分型的SNPs的识别将是可能的。

Telomeres consist of long TTAGGG nucleotide repeats and associated proteins at the ends of chromosomes that are essential for the maintenance of chromosomal integrity. In order to preserve the chromosome end, the telomerase reverse transcriptase (TERT), its RNA component (TERC) and an ordered protein complex, termed shelterin, consisting of six proteins (gene names: TERF1, TERF2, TINF2, TERF2IP, ACD and POT1) protect the telomere from end-to-end fusion. Telomeric repeats are lost with each cell division, in part due to incomplete replication of the 3" end of the chromosome. Telomeric attrition eventually results in critically short telomeres prompting cellular senescence or cellular crisis, including apoptosis, genomic instability or a reduction in cellular lifespan. 1) Dyskeratosis congenita (DC) study: DC is an inherited bone marrow failure syndrome (IBMFS) and cancer predisposition disorder characterized by abnormalities in telomere biology and caused by germ-line mutations in one of several genes in the telomere pathways. We recently showed that telomere length, as measured by flow cytometry-FISH was both sensitive and specific for differentiation DC from other IBMFS. Identifying novel genes which might account for the 60% of DC patients who currently do not have detectable mutations in DKC1, TERC or TERT is one of the major goals of this study. Our recently completed a linkage study which has identified TINF2 as mutated in several families with DC. This study also focuses on careful clinical phenotyping. A comprehensive study of dysmorphology in DC is also underway. These studies will provide more specific data on genotype-phenotype interactions and aid in diagnosis of DC. 2) Telomere length in target tissues: These are a set of small, methodological studies that seek to clarify intra-individual variability in telomere length with the ultimate goal being improved understanding of comparability when different cell types and methods of telomere length determination are employed. Epidemiologic studies typically use DNA isolated from either blood or buccal cells, yet direct comparisons of telomere length in blood and buccal cell DNA have not been published. This study will evaluate intra- and inter- individual variation in telomere length in blood, buccal cell and fibroblast DNA in subjects enrolled in the inherited bone marrow failure syndromes study. It will also study the telomere length differences between buccal cell and blood DNA in healthy controls from an ovarian cancer study. 3) Telomere length as a risk factor for prostate cancer: Telomeres, telomere shortening and telomerase activity have emerged as important factors in prostate carcinogenesis. The earliest phase of human prostate carcinogenesis may proceed as a consequence of chromosomal instability mediated by shortened, dysfunctional telomeres. This is part of a case-control study of prostate cancer from the PLCO cohort. Telomere length was determined on 1200 controls and 700 cases of advanced prostate cancer Strong associations between telomere length and prostate cancer risk were not identified. However, longer telomeres were associated with a healthier lifestyle. 4) Novel genetic determinants of telomere length: The same subjects described in 3 were also part of a genome-wide association study (CGEMS, Cancer Genetic Markers of Susceptibility). In collaboration with Drs. Immaculata DeVivo and David Hunter (Harvard School of Public Health), we will add 1200 healthy controls from the Nurse"s Health Study who were part of the CGEMS breast cancer whole-genome scan. We are evaluating the relationship between genetic variants measured on the same platform in the CGEMS GWAS and telomere length (both measured in the same laboratory) among healthy controls: 1200 men and 1200 women. Lastly, interactions between genotypes affecting telomere length will be assessed in the prostate cancer cases and controls. . 5) Population genetics of telomere genes: We have previously shown that nucleotide diversity is low in genes important in telomere biology. This study will follow-up on those finding by evaluating genetic variation in more than 30 telomere biology genes in 1000 individuals from around the world. Insights into population history and identification of SNPs for genotyping in case-control studies will be possible..