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核苷酸重复序列和相关蛋白组成，在染色体的末端，对于维持染色体完整性至关重要。为了保留染色体末端，端粒酶逆转录酶（TERT），其RNA成分（TERC）和有序的蛋白质复合物，称为庇护素，称为庇护素，由六种蛋白质（基因名称：TERF1，TERF1，TERF2，TINF2，TINF2，TINF2，TERF2IP，ACD和POT1）保护远距离触发。每种细胞分裂都会丢失端粒重复，部分原因是染色体的3“末端的复制不完整。端粒损耗最终导致近距离端粒促使细胞衰老或细胞危机促使端粒造成较短（IBMF）和癌症易感障碍，其特征是端粒生物学异常，并由端粒途径中的几个基因中的一种生殖线突变引起，我们最近表明，通过流式细胞仪较高的态度，端粒长度既易于识别ibmf，又是鉴定出差异的人。 DKC1，TERC或TERT是我们最近完成的链接研究的主要目标。是一组小型的方法论研究，旨在阐明端粒长度的内部变异性，而最终目标是对端粒长度确定的不同细胞类型和方法的理解，而不是使用血液或脉络电细胞的比较，则使用了tebormere dna。在遗传的骨髓衰竭综合征中，血液，颊细胞和成纤维细胞DNA的端粒长度的变化还将研究卵巢癌的远期远期因素和远离型号的远期因素：远期的远期因素：远距离癌症。前列腺癌的最早，前列腺癌的最早，可能是由于较短的，功能障碍的端粒介导的染色体不稳定性。但是，较长的端粒与健康的生活方式相关。 CGEM乳腺癌全基因组扫描。我们正在评估健康对照中的CGEMS GWAS和端粒长度（均在同一实验室中测量的）在同一平台上测量的遗传变异之间的关系：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）端粒基因的种群遗传学：我们先前已经表明，核苷酸的多样性在端粒生物学中重要的基因较低。这项研究将通过评估来自世界上1000多个端粒生物学基因的遗传变异来进行对那些发现的跟进。可以在病例对照研究中对人群史和SNP进行基因分型的识别。

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