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: 10007433
• 负责人: Sharon A. Savage
• 金额: $ 60.43万
• 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/10007433
• 关键词: Aplastic Anemia; Area; Biology; Blood; Cancer Etiology; Case-Control Studies; Cells; Chromosome abnormality; Clinical; Cohort Studies; Collaborations; Complex; DNA; Data; Defect; Diagnostic; Disease; Dyskeratosis Congenita; Enrollment; Epidemiology; Epigenetic Process; Etiology; Evaluation; Family; Family member; Fanconi' s Anemia; Fibroblasts; Gene Expression Regulation; Genes; Genetic Determinism; Genetic Population Study; Germ-Line Mutation; Goals; Head and Neck Cancer; Heterogeneity; Human; Individual; Inherited; Length; Leukocytes; Link; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Marrow; Measures; Medical Genetics; Meta-Analysis; Methodological Studies; Molecular; Mutation; Nail plate; Oral Leukoplakia; Outcome; Pancytopenia; Participant; Pathogenesis; Patients; Pattern; Pigmentation physiologic function; Pilot Projects; Play; Population Genetics; Predisposition; Prior Therapy; Prospective Studies; Proteins; Recording of previous events; Resources; Retrospective Studies; Risk; Risk Factors; Role; Site; Stem cell transplant; Syndrome; TINF2 gene; Telomerase; Telomere Maintenance; Tissues; Universities; Variant; Work; bone marrow failure syndrome; cancer risk; cancer site; cancer therapy; case control; clinical phenotype; cohort; design; disorder risk; exome sequencing; genetic epidemiology; genetic pedigree; genetic variant; genome wide association study; human disease; insight; malignant breast neoplasm; malignant stomach neoplasm; medical complication; novel; peripheral blood; programs; repository; sample collection; telomere

The Dyskeratosis congenita (DC) [CAS 10374] study provides comprehensive clinical and molecular evaluations to patients with DC and their family members, to better understand the role of telomere biology defects in this disorder. DC is an inherited bone marrow failure syndrome (IBMFS) characterized by abnormal nails, lacey reticular pigmentation, oral leukoplakia, very short telomeres, and significantly elevated risks of aplastic anemia and cancer. Family pedigrees in DC indicate that there are multiple modes of inheritance (e.g. X-linked, autosomal dominant and autosomal recessive), although many cases are sporadic (i.e., lack a family history). We have discovered four novel causes of DC: (1) Germline mutations in TINF2 provided the first evidence that disruption of the shelterin protein protection complex can cause human disease; (2) DC-causing mutations in WRAP53 were first proof that mislocalization of telomerase could cause human illness. (3) Exome sequencing discovered mutations in RTEL1, a DNA helices and telomere biology gene, as a novel cause of DC, and (4) We also showed that mutations in another component of shelterin, TPP1, encoded by ACD cause DC and result in telomerase processivity defects. All participants in the DC cohort are evaluated for mutations in the DC-associated genes. We perform targeted gene sequencing and whole exome sequencing to discover the causes of DC in all enrolled families. Our DC studies have been used to demonstrate that very short telomeres (by Flow-FISH) in peripheral blood leukocyte subsets comprise a diagnostic abnormality for this disorder. Analysis of the cancers in these families demonstrates a pattern that is strikingly similar to that observed in Fanconi anemia (i.e., MDS, AML, squamous cell cancers of the head/neck and anorectal cancers). The DC Biospecimen Repository is a rich resource used to understand the molecular consequences of telomere biology abnormalities. We are also exploring several new hypotheses related to DC pathogenesis, including epigenetic gene regulation and chromosomal abnormalities. Detailed characterization of the clinical phenotype and medical complications is ongoing. Telomere Length in Target Tissues [CAS 10373] is now closed. It evaluated intra-individual telomere length measured by QPCR of DNA derived from blood, buccal cells, and fibroblasts from IBMFS patients as well as the correlation between flow-FISH and QPCR. It found that in general, fibroblast telomeres were longer than blood or buccal cell telomeres but that there was significant intra-individual correlation between tissue types. This pilot study forms the basis for larger methodological studies of telomere biology and cancer risk. We are also investigating Telomere Length as Cancer Risk Factor [CAS 10371]. Numerous studies suggest that short surrogate tissue TL is a cancer risk factor. Our previous case-control studies found that short telomeres are associated with increased risk of ovarian and gastric cancer. However, our cohort study of TL and prostate cancer did not find the same association. Our meta-analysis on the association between TL in surrogate tissues and cancer risk which suggests short TL and overall cancer are associated but this may be driven by stronger effects in specific cancers. The ORs derived from retrospective studies were much higher than for prospective studies (2.9 versus 1.16), which suggests reverse causation bias and possible contribution of cancer therapy prior to sample collection. Study heterogeneity and minimal or no data on certain cancer sites were also limitations of these analyses. Ongoing work includes many collaborative studies of TL and cancer designed to 1) determine if TL is associated with risk of specific cancers or cancer-related outcomes, 2) determine differences in TL and cancer associations in case-control versus cohort studies, and 3) use these studies as building blocks for germline (i.e., surrogate) and somatic tissue studies aimed at better understanding the contribution of telomere biology to cancer etiology Genetic Variants That Correlate With Telomere Length [CAS 10371] have been evaluated through analyses of SNP data derived from the NCI CGEMS GWAS of prostate and breast cancer. We found that 13 SNPs from 4 genes were associated with TL. We also collaborated with Harvard University on a genome-wide association study (GWAS) of TL. That study confirmed a SNP in TERC as associated with TL, but, similar to other studies, did not find strong associations between SNPs at other sites and TL. A new project, Telomere length after HSCT in patients with acquired severe aplastic anemia [CAS 10508] was initiated which seeks to understand the role of telomere biology in outcomes after hematopoictic stem cell transplant (HCT) for acquired severe aplastic anemia (SAA). In collaboration with the National Marrow Donor Program (NMDP), we showed that donor TL is significantly associated with clinical outcomes in patients undergoing HCT for SAA. Ongoing analyses seek to validate these findings in other patients undergoing HCT. Population genetic studies of telomere biology genes [CAS 10372] continue to provide important insight into their evolutionary history. Ongoing studies include characterization of the functional consequences of germline variants in telomere biology genes and correlation with clinical findings.

DC的脑膜炎兴奋剂（DC）[CAS 10374]研究为DC及其家人及其家人的患者提供了全面的临床和分子评估，以更好地了解端粒生物学缺陷在这种疾病中的作用。 DC是一种遗传性的骨髓衰竭综合征（IBMFS），其特征在于指甲异常，蕾丝网状色素沉着，口服白细胞，端粒非常短，以及相性贫血和癌症的风险显着升高。 DC中的家族血统表明，尽管许多病例是零星的（即缺乏家族史），但有多种继承模式（例如，X连锁，常染色体显性和常染色体隐性）。 我们发现了DC的四个新原因：（1）TINF2中的种系突变提供了第一个证据，表明庇护素蛋白保护蛋白保护络合物的破坏会导致人类疾病。 （2）WRAP53中引起DC的突变首先证明了端粒酶的错误定位可能导致人类疾病。 （3）在RTEL1，DNA螺旋和端粒生物学基因的RTEL1中发现的外显子组测序是DC的新原因，（4）我们还表明，Shelterin的另一个成分TPP1中的突变，TPP1，由ACD导致DC编码，并导致端粒酶过程缺陷。 DC队列中的所有参与者均评估与DC相关基因中的突变。我们执行靶向基因测序和整个外显子组测序，以发现所有参与家庭的DC的原因。我们的DC研究已被用来证明外周血白细胞中很短的端粒（通过流动）构成了这种疾病的诊断异常。对这些家族中癌症的分析表明，一种模式与在Fanconi贫血中观察到的模式非常相似（即MDS，AML，头部/颈部的鳞状细胞癌和肛门直肠癌）。直流生物循环库是一种丰富的资源，用于了解端粒生物学异常的分子后果。我们还正在探索与DC发病机理有关的几种新假设，包括表观遗传基因调节和染色体异常。临床表型和医疗并发症的详细表征正在进行中。靶组织中的端粒长度[CAS 10373]现已关闭。它评估了通过源自血液，颊细胞衍生的DNA和IBMFS患者的成纤维细胞的QPCR测量的个体内端粒长度，以及流动菌与QPCR之间的相关性。它发现通常，成纤维细胞端粒比血液或颊细胞端粒更长，但组织类型之间存在显着的个体内相关性。这项试验研究构成了端粒生物学和癌症风险的大量方法论研究的基础。我们还正在研究端粒长度作为癌症危险因素[CAS 10371]。大量研究表明，短替代组织TL是癌症危险因素。我们以前的病例对照研究发现，短端粒与卵巢癌和胃癌的风险增加有关。但是，我们对TL和前列腺癌的队列研究并未发现相同的关联。我们对替代组织中TL与癌症风险之间关联的荟萃分析表明，短TL和整体癌症是相关的，但这可能是由于特定癌症的较强作用而驱动的。从回顾性研究中得出的OR远高于前瞻性研究（2.9对1.16），这表明在采集样本之前，逆转因果偏差和癌症治疗的可能贡献。研究异质性和对某些癌症部位的最小或没有数据也是这些分析的局限性。正在进行的工作包括许多针对TL和癌症的协作研究。1）确定TL是否与特定的癌症或与癌症相关结果的风险有关，2）确定病例对照中TL和癌症关联的差异与同类群体研究，以及3）使用这些研究作为生物学的基础（即更好地理解造成癌症）的基础，以了解促进癌症的范围。与端粒长度相关的[CAS 10371]已通过分析从前列腺和乳腺癌的NCI CGEMS GWAS得出的SNP数据进行了评估。我们发现来自4个基因的13个SNP与TL相关。我们还与哈佛大学合作进行了全基因组协会研究（GWAS）的TL。该研究证实了TERC中的SNP与TL相关，但是与其他研究类似，在其他站点和TL之间并未发现SNP之间的牢固关联。启动了一个新的项目，即HSCT后HSCT后的端粒长度[CAS 10508]，旨在了解造血性干细胞移植（HCT）的端粒生物学在结果中的作用，以获得严重的性质感贫血（SAA）。通过与国家骨髓供体计划（NMDP）合作，我们表明供体TL与SAA HCT患者的临床结果显着相关。正在进行的分析试图在其他正在接受HCT的患者中验证这些发现。端粒生物学基因的人群遗传研究[CAS 10372]继续为其进化史提供重要的见解。正在进行的研究包括表征端粒生物学基因种系变异的功能后果以及与临床发现的相关性。