Genetic Epidemiology of Telomere Maintenance and Cancer Etiology

端粒维持的遗传流行病学和癌症病因学

• 批准号: 7733744
• 负责人: Sharon A. Savage
• 金额: $ 2.31万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733744
• 关键词: Accounting; Affect; Apoptosis; Biology; Blood; Blood Cells; Cancer Etiology; Case-Control Studies; Categories; Cell Aging; Cell division; Cells; Chromosomal Instability; Chromosomes; Collaborations; Colon, Rectum; Complex; DNA; Data; Diagnosis; Disease; Dyskeratosis Congenita; Dysmorphology; Enrollment; Epidemiologic Studies; Family; Fibroblasts; Flow Cytometry; Gene Proteins; Genes; Genetic Determinism; Genetic Markers; Genetic Variation; Genomic Instability; Genotype; Germ-Line Mutation; Goals; Individual; Inherited; Laboratories; Length; Life Style; Longevity; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Measures; Mediating; Methodological Studies; Methods; Mutate; Mutation; Names; Nucleotides; Nurses' Health Study; Pancytopenia; Patients; Phase; Phenotype; Play; Population; Population Genetics; Predisposition; Prostate; Proteins; Public Health Schools; Publishing; RNA; Range; Recording of previous events; Risk Factors; Role; Single Nucleotide Polymorphism; Syndrome; TERF1 gene; TERF2 gene; TINF2 gene; Telomerase; Telomere Maintenance; Telomere Pathway; Telomere Shortening; Tissues; Variant; Woman; cancer genetics; cancer risk; carcinogenesis; case control; cell type; clinical phenotype; cohort; disease-causing mutation; follow-up; genetic epidemiology; genetic variant; genome wide association study; human TERF1 protein; human TERF2 protein; improved; insight; malignant breast neoplasm; men; novel; telomerase reverse transcriptase; telomere

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..

端粒由长TTAGGG核苷酸重复序列和染色体末端的相关蛋白组成，对维持染色体完整性至关重要。为了保护染色体末端，端粒酶逆转录酶（TERT）、其RNA组分（TERC）和一种有序的蛋白质复合物，称为庇护蛋白，由六种蛋白质（基因名称：TERF1、TERF2、TINF2、TERF2IP、ACD和POT1）组成，保护端粒免受端到端融合。每次细胞分裂都会丢失端粒重复序列，部分原因是染色体3 '末端的复制不完全。端粒损耗最终导致端粒极短，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，其特征是端粒生物学异常，由端粒通路中几个基因之一的种系突变引起。我们最近发现，通过流式细胞术- fish测量的端粒长度对DC与其他IBMFS的分化既敏感又特异性。寻找可能解释60%目前未检测到DKC1、TERC或TERT突变的DC患者的新基因是本研究的主要目标之一。我们最近完成了一项连锁研究，发现TINF2在几个DC家族中发生突变。本研究还侧重于仔细的临床表型。对DC畸形学的全面研究也在进行中。这些研究将为基因型-表型相互作用提供更具体的数据，并有助于DC的诊断。2)靶组织的端粒长度：这是一组小型方法学研究，旨在阐明端粒长度的个体内变异性，最终目标是提高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分离的DNA，然而，血液和口腔细胞DNA端粒长度的直接比较尚未发表。本研究将评估参加遗传性骨髓衰竭综合征研究的受试者血液、颊细胞和成纤维细胞DNA端粒长度的个体内和个体间差异。它还将研究一项卵巢癌研究中健康对照者颊细胞和血液DNA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缩短的功能失调的端粒介导的染色体不稳定的结果。这是来自PLCO队列的前列腺癌病例对照研究的一部分。对1200例对照和700例晚期前列腺癌患者的端粒长度进行了测定，端粒长度与前列腺癌风险之间的强烈关联尚未确定。然而，更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中描述的相同受试者也是全基因组关联研究（CGEMS，癌症易感性遗传标记）的一部分。在与博士合作。Immaculata DeVivo和David Hunter（哈佛大学公共卫生学院），我们将加入1200名来自护士健康研究的健康对照，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遗传变异与端粒长度之间的关系（两者都在同一实验室测量），健康对照：1200名男性和1200名女性。最后，将在前列腺癌病例和对照组中评估影响端粒长度的基因型之间的相互作用。5)端粒基因的群体遗传学：我们之前已经表明，在端粒生物学中重要基因的核苷酸多样性很低。这项研究将通过评估来自世界各地1000个人的30多个端粒生物学基因的遗传变异来跟踪这些发现。在病例对照研究中，深入了解人群历史和snp的基因分型将成为可能。

项目成果

The evidence for prostate cancer risk loci at 8q24 grows stronger.

8q24 处前列腺癌风险位点的证据越来越充分。

• DOI: 10.1093/jnci/djm186
• 发表时间: 2007
• 期刊: Journal of the National Cancer Institute
• 作者: Savage,SharonA;Greene,MarkH
• 通讯作者: Greene,MarkH