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: 8349586
• 负责人: Sharon A. Savage
• 金额: $ 91.2万
• 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/8349586
• 关键词: 5p15.33; Aplastic Anemia; Area; Biology; Blood; Cancer Etiology; Case-Control Studies; Cell Nucleus; Cells; Cessation of life; 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; Flow Cytometry; Fluorescent in Situ Hybridization; Gene Expression Regulation; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Population Study; Genetic Variation; Genome; Goals; Haplotypes; Head and neck structure; Heterogeneity; Histocompatibility Testing; Human Genome; Impairment; Individual; Inherited; Length; Leukocytes; Link; Linkage Disequilibrium; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Marrow; Measures; Meta-Analysis; Methodological Studies; Molecular; Molecular Genetics; Mutation; Nail plate; Names; Oral Leukoplakia; Outcome; Pancytopenia; Participant; Pathogenesis; Patients; Pattern; Pigmentation physiologic function; Pilot Projects; Play; Population; Population Genetics; Predisposition; Prospective Studies; Proteins; Publishing; Recording of previous events; Research; Retrospective Studies; Risk; Risk Factors; Role; Site; Stem cell transplant; Syndrome; TERT gene; TINF2 gene; Technology; Telomerase; Telomere Maintenance; Tissues; Transplant Recipients; Transplantation; Universities; Variant; Work; base; cancer risk; cancer site; cancer therapy; case control; clinical phenotype; cohort; design; disorder risk; genetic epidemiology; genetic pedigree; genetic variant; genome wide association study; improved; insight; international center; malignant breast neoplasm; malignant stomach neoplasm; medical complication; next generation; novel; peripheral blood; programs; 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 discovered, in 2008, that mutations in TINF2, a component of the shelterin telomere protection complex, cause autosomal dominant DC. In 2010, we discovered that compound heterozygous mutations in telomere cajal body protein 1 (TCAB1, gene name WRAP53) cause DC through impairment of telomerase localization in the nucleus. All families with DC enrolled in the NCIs IBMFS study are evaluated for mutations in the known DC genes: TINF2, DKC1, TERC, TERT, NOP10, NHP2, and WRAP53.. All participants in the DC cohort are evaluated for mutations in the DC-associated genes. However, nearly 50% of our patients are mutation-negative. Our ongoing work includes use of next-generation sequencing technologies to identify the genetic causes of DC in mutation-negative 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). 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 fluorescence in situ hybridization with flow-cytometry, (flow-FISH). As expected, patients with dyskeratosis congenita had the shortest telomeres. We 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. We conducted a meta-analysis in which we systematically reviewed studies published prior to August 30, 2010 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 (HSCT) for acquired severe aplastic anemia (SAA). Pre-transplant TL has been measured in controls, donors, and HSCT recipients in collaboration with the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow transplant research (CIBMTR). Ongoing analyses include the association of TL with HSCT outcomes such as death, post-transplant malignancies, and fibrotic diseases. Population genetic studies of telomere biology genes [CAS 10372] continue to provide important insight into their evolutionary history. This will improve understanding of the role of genetic variation in their function and aid in understanding these variants as cancer risk factors. We expanded on our initial study of seven genes by evaluating 37 telomere biology genes in 53 worldwide populations utilizing SNP data from the Human Genome Diversity Panel. This study showed that, as a group, telomere biology genes have low to moderate haplotype diversity, high ancestral allele frequencies, and low differentiation. The telomerase gene (TERT) was a notable exception with low levels of linkage disequilibrium. Evidence suggestive of evolutionary selection was present in five genes. Ongoing studies include detailed studies of genetic variation in the 5p15.33 chromosomal locus using 1000 Genomes data. This locus includes TERT and CLPTM1L and includes SNPs which have been associated with cancer risk in several GWAS.

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）。我们在2008年发现，TINF2中的突变是庇护素端粒保护综合体的一个组成部分，引起了常染色体显性DC。在2010年，我们发现端粒Cajal体蛋白1（TCAB1，Gene Name Wrap53）中的复合杂合突变通过在细胞核中的端粒酶定位受损而导致DC。在NCIS IBMFS研究中均参与了所有DC的所有家庭均评估了已知的DC基因中的突变：TINF2，DKC1，TERC，TERC，TERT，NOP10，NHP2和WRAP53。所有DC同学中的所有参与者均在DC相关基因中的突变进行评估。但是，我们近50％的患者是突变阴性。我们正在进行的工作包括使用下一代测序技术来识别突变阴性家族中直流的遗传原因。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）。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患者的成纤维细胞测量的个体内端粒长度，以及与流量仪的原位杂交荧光原位杂交之间的相关性。正如预期的那样，隆古尼塔病患者的端粒最短。我们发现，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。我们进行了一项荟萃分析，在2010年8月30日之前，我们有系统地审查了替代组织中TL与癌症风险之间的关联，这表明TL和整体癌症是相关的，但这可能是由在特定癌症中更强烈的影响驱动的。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]，旨在了解催化性干细胞移植（HSCT）的端粒生物学在结果中的作用，用于获得性严重的性同性贫血（SAA）。移植前TL已与国家骨髓供体计划（NMDP）和国际血液和骨髓移植研究中心（CIBMTR）合作，在对照，供体和HSCT接受者中测量。正在进行的分析包括TL与HSCT结果的关联，例如死亡，移植后恶性肿瘤和纤维化疾病。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。这将提高人们对遗传变异在其功能中的作用的理解，并有助于将这些变体视为癌症风险因素。我们通过评估来自人类基因组多样性小组中SNP数据的53个全球人群中的37个端粒生物学基因，扩展了对七个基因的初步研究。这项研究表明，作为一个小组，端粒生物学基因具有低至中度单倍型的多样性，高祖先等位基因频率和低分化。端粒酶基因（TERT）是一个很明显的例外，连锁不平衡。五个基因中存在暗示进化选择的证据。正在进行的研究包括使用1000个基因组数据的5p15.33染色体基因座遗传变异的详细研究。该基因座包括TERT和CLPTM1L，其中包括与多个GWAS癌症风险有关的SNP。