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，对于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 成分 (TERC) 和有序蛋白质复合物（称为庇护蛋白）由六种蛋白质组成（基因名称：TERF1、TERF2、TINF2、TERF2IP、ACD 和 POT1） ）保护端粒免于端到端融合。每次细胞分裂时，端粒重复序列都会丢失，部分原因是染色体 3" 末端复制不完整。端粒磨损最终导致端粒极短，从而引发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 .我们最近表明，通过流式细胞术-FISH 测量的端粒长度对于鉴别 DC 与其他 IBMFS 的新基因既敏感又特异。这项研究的主要目标之一是减少目前在 DKC1、TERC 或 TERT 中未检测到突变的 DC 患者，该研究已确定 TINF2 在几个家族中发生突变。与直流电。这项研究还侧重于仔细的临床表型分析。对 DC 畸形的全面研究也在进行中。这些研究将提供有关基因型-表型相互作用的更具体数据，并有助于 DC 的诊断。 2) 目标组织中的端粒长度：这是一组小型的方法学研究，旨在阐明端粒长度的个体内部变异性，最终目标是提高对采用不同细胞类型和端粒长度测定方法时的可比性的理解。流行病学研究通常使用从血液或口腔细胞中分离的 DNA，但血液和口腔细胞 DNA 中端粒长度的直接比较尚未发表。本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者口腔细胞和血液 DNA 之间的端粒长度差异。 3）端粒长度作为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缩短、功能失调介导的染色体不稳定造成的。这是 PLCO 队列前列腺癌病例对照研究的一部分。对 1200 名对照者和 700 名晚期前列腺癌病例测定了端粒长度。尚未发现端粒长度与前列腺癌风险之间的强关联。然而，较长的端粒与更健康的生活方式相关。 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，癌症遗传易感性标记）的一部分。与博士合作。 Immaculata DeVivo 和 David Hunter（哈佛大学公共卫生学院），我们将添加来自护士健康研究的 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 中的同一平台和健康对照中的端粒长度（均在同一实验室测量）：1200 名男性和 1200 名女性最后，之间的相互作用。影响端粒长度的基因型将在前列腺癌病例和对照中进行评估。 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的基因中核苷酸多样性较低。评估来自世界各地 1000 名个体的 30 多个端粒生物学基因的遗传变异，并在病例对照研究中鉴定用于基因分型的 SNP。 可能的..

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