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.

先天性角化不良 (DC) [CAS 10374] 研究为 DC 患者及其家庭成员提供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 是一种遗传性骨髓衰竭综合征 (IBMFS)，其特征是指甲异常、花边网状色素沉着、口腔白斑、端粒非常短以及再生障碍性贫血和癌症的风险显着升高。 DC 的家族谱系表明存在多种遗传模式（例如 X 连锁遗传、常染色体显性遗传和常染色体隐性遗传），尽管许多病例是散发性的（即缺乏家族史）。 2008 年，我们发现 TINF2（庇护蛋白端粒保护复合物的一个组成部分）的突变会导致常染色体显性 DC。 2010年，我们发现端粒cajal体蛋白1（TCAB1，基因名称WRAP53）的复合杂合突变通过损害端粒酶在细胞核中的定位而导致DC。对参加 NCI IBMFS 研究的所有 DC 家族进行已知 DC 基因突变评估：TINF2、DKC1、TERC、TERT、NOP10、NHP2 和 WRAP53。相关基因。然而，我们近 50% 的患者突变呈阴性。我们正在进行的工作包括使用下一代测序技术来确定突变阴性家族中 DC 的遗传原因。我们的 DC 研究已用于证明外周血白细胞亚群中非常短的端粒（通过 Flow-FISH）构成了该疾病的诊断异常。对这些家族中癌症的分析表明，其模式与范可尼贫血（即MDS、AML、头/颈鳞状细胞癌和肛门直肠癌）中观察到的模式惊人相似。我们还在探索与 DC 发病机制相关的几个新假设，包括表观遗传基因调控和染色体异常。临床表型和医学并发症的详细表征正在进行中。目标组织中的端粒长度 [CAS 10373] 现已关闭。它评估了通过 QPCR 对来自 IBMFS 患者的血液、口腔细胞和成纤维细胞的 DNA 测量的个体内端粒长度，以及荧光原位杂交与流式细胞术 (flow-FISH) 之间的相关性。正如预期的那样，先天性角化不良患者的端粒最短。我们发现，一般来说，成纤维细胞端粒比血液或口腔细胞端粒长，但组织类型之间存在显着的个体内相关性。这项初步研究为端粒生物学和癌症风险的更大规模方法学研究奠定了基础。我们还在研究端粒长度作为癌症风险因素的作用 [CAS 10371]。大量研究表明，短替代组织 TL 是癌症危险因素。我们之前的病例对照研究发现，端粒短与卵巢癌和胃癌的风险增加有关。然而，我们的 TL 和前列腺癌队列研究并未发现相同的关联。我们进行了一项荟萃分析，系统回顾了 2010 年 8 月 30 日之前发表的关于替代组织中 TL 与癌症风险之间关联的研究，表明短 TL 与整体癌症相关，但这可能是由特定癌症中更强的影响驱动的。回顾性研究得出的 OR 远高于前瞻性研究（2.9 比 1.16），这表明反向因果偏倚以及样本收集之前癌症治疗的可能贡献。研究异质性以及某些癌症部位的数据很少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 TL 和癌症的合作研究，旨在 1) 确定 TL 是否与特定癌症或癌症相关结果的风险相关，2) 确定病例对照研究与队列研究中 TL 和癌症关联的差异，以及 3)使用这些研究作为种系（即替代）和体细胞组织研究的基础，旨在更好地了解端粒生物学对癌症病因学的贡献与端粒长度相关的遗传变异[CAS 10371] 已通过分析源自前列腺癌和乳腺癌的 NCI CGEMS GWAS 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开展了 TL 的全基因组关联研究 (GWAS)。该研究证实了 TERC 中的 SNP 与 TL 相关，但与其他研究类似，没有发现其他位点的 SNP 与 TL 之间存在很强的关联。启动了一个新项目，即获得性严重再生障碍性贫血患者 HSCT 后的端粒长度 [CAS 10508]，旨在了解端粒生物学在获得性严重再生障碍性贫血 (SAA) 造血干细胞移植 (HSCT) 后结果中的作用。与国家骨髓捐赠计划 (NMDP) 和国际血液和骨髓移植研究中心 (CIBMTR) 合作，测量了对照、捐赠者和 HSCT 接受者的移植前 TL。正在进行的分析包括 TL 与 HSCT 结果（如死亡、移植后恶性肿瘤和纤维化疾病）之间的关系。端粒生物学基因的群体遗传学研究 [CAS 10372] 继续为了解其进化历史提供重要的见解。这将增进对遗传变异在其功能中的作用的理解，并有助于将这些变异理解为癌症危险因素。我们利用人类基因组多样性小组的 SNP 数据评估了全球 53 个人群中的 37 个端粒生物学基因，扩展了对 7 个基因的初步研究。这项研究表明，作为一个群体，端粒生物学基因具有低至中等的单倍型多样性、高祖先等位基因频率和低分化。端粒酶基因（TERT）是一个显着的例外，其连锁不平衡水平较低。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 个基因组数据对 5p15.33 染色体位点的遗传变异进行详细研究。该基因座包括 TERT 和 CLPTM1L，并包括在多个 GWAS 中与癌症风险相关的 SNP。