THE MOLECULAR BASIS OF ROTHMUND-THOMSON SYNDROME AND OSTEOSARCOMA

罗斯蒙-汤姆森综合征和骨肉瘤的分子基础

• 批准号: 8356707
• 负责人: LISA WANG
• 金额: $ 0.12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356707
• 关键词: Accounting; Adolescent; Affect; Ataxia Telangiectasia; Baller-Gerold syndrome; Biology; Blood; Bloom Syndrome; Body Fluids; Bone neoplasms; Cataract; Child; Clinical; Clinical Data; Clinical Research; Collection; Constitutional; DNA biosynthesis; Data; Defect; Dental; Development; Disease; Dyskeratosis Congenita; Enrollment; Eyebrow structure; Family member; Fanconi' s Anemia; Funding; Gene Mutation; General Population; Genes; Genetic; Genetic Heterogeneity; Genetic Materials; Genetic Predisposition to Disease; Genome Stability; Genotype; Goals; Grant; Hair; Hereditary Disease; Hereditary Malignant Neoplasm; Hereditary Retinoblastoma; Inborn Genetic Diseases; Li-Fraumeni Syndrome; Maintenance; Malignant Bone Neoplasm; Malignant Neoplasms; Medical; Medical Records; Molecular; Molecular Genetics; Mutation; National Center for Research Resources; Normal tissue morphology; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Predisposition; Principal Investigator; Proteins; Protocols documentation; RECQL4 gene; Rare Diseases; Relative (related person); Research; Research Infrastructure; Research Personnel; Resources; Risk; Role; Rothmund-Thomson syndrome; Sampling; Scalp structure; Skeletal Development; Source; Specimen; Syndrome; United States National Institutes of Health; Werner Syndrome; Xeroderma Pigmentosum; base; bone; cancer type; cost; design; gastrointestinal; high risk; insight; interest; osteosarcoma; sample collection; skeletal; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Certain genetic syndromes are known to predispose affected patients to cancer more than the general population. Rothmund-Thomson syndrome (RTS) is one of these cancer syndromes and specifically predisposes patients to developing osteosarcoma (OS), a primary bone tumor that occurs in children and adolescents. Mutations in a gene called RECQL4 accounts for two-thirds of cases of RTS; however, for the other one-third of patients, the gene defect has not yet been discovered. We are interested in studying patients with RTS and related syndromes, as well as patients with atypical forms of OS, in order to understand the molecular mechanisms underlying OS predisposition and pathogenesis. This study would allow the collection of samples and medical information from patients with RTS and related disorders and their family members, as well as from patients with atypical osteosarcoma that may have a genetic basis, so that molecular and genetic studies can be conducted to better understand the primary syndrome (RTS), the predisposition toward cancer development, as well as the molecular pathogenesis of OS. I. HYPOTHESIS Studying rare cancer predisposition syndromes (RTS) both at the clinical and molecular level will provide insight into the pathogenesis of cancer (OS) in the general population. II. SPECIFIC AIMS Specific Aim 1: Collect and analyze clinical samples from patients affected by RTS and related syndromes and atypical forms of OS as well as their family members. Samples would include blood, tissues (normal and tumor) and body fluids which would be made available to investigators for the purpose of conducting research that will help to define and characterize the underlying genetic defects which cause these inherited disorders and their propensity toward cancer. Specific Aim 2: Collect and analyze medical records from patients affected by RTS and related syndromes and atypical forms of OS as well as their family members. Clinical information will allow genotype-phenotype analyses in combination with molecular studies. III. BACKGROUND AND SIGNIFICANCE RTS is a genetic disorder that belongs to a class of familial cancer predisposition syndromes including ataxia-telangiectasia, Fanconi anemia, xeroderma pigmentosum, dyskeratosis congenita, Bloom syndrome, and Werner syndrome. Patients with these disorders all have known genetic defects that place them at an increased risk for certain types of cancers. RTS patients are particularly prone to developing OS, a primary malignant bone tumor. They may also have other clinical features such as poikiloderma, small stature, skeletal defects, sparse or absent scalp hair, eyebrows or lashes, juvenile cataracts, gastrointestinal disturbances, and dental abnormalities. The molecular basis of RTS is known for a subset (approximately 2/3rds) of patients and involves mutation of the RECQL4 gene. The molecular basis for the other 1/3 of patients is not currently known, but likely involves mutation of another gene or genes (genetic heterogeneity). The function of the RECQL4 protein is not fully understood, but it is believed to play a role in DNA replication and in the maintenance of genomic stability. Among RTS patients, those who carry truncating mutations in the RECQL4 gene are at significantly higher risk of developing OS and of having bone defects compared to RTS patients without RECQL4 mutations. Thus the RECQL4 gene pathway is felt to play a role in the pathogenesis of OS and skeletal development. Several other genes, including p53 and RB, are thought to play central roles in the pathogenesis of sporadic OS, and constitutional mutations of these genes are responsible for Li-Fraumeni Syndrome and hereditary retinoblastoma, respectively. Both of these syndromes are also associated with an increased risk for OS, but neither carries a higher or more specific risk for OS than RTS. Recently two other syndromes, RAPADILINO syndrome and Baller-Gerold syndrome (BGS), have also been found to be caused in some cases by mutations in RECQL4; however, the risk for OS in these syndromes has not yet been defined. For RTS as well as the other familial cancer predisposition syndromes, there is a continued need to collect and generate primary data both at the clinical and molecular levels in order to understand the underlying molecular defects and the clinical consequences particularly in relation to cancer. Because these are rare disorders worldwide, accumulating data on affected patients and their relatives in order to study their genetic material becomes a difficult task. The purpose of this study is the collection and analysis of clinical data and biologic specimens from patients affected by RTS and related disorders or unusual forms of OS, as well as their family members. One of the major long-term goals of this project is to further understanding of the biology of OS through the study of patients with RTS or other RECQL4 disorders. Previously patients with RTS were enrolled in a broader study entitled The Molecular Basis of Familial Cancer Predisposition Syndromes (H-7207). Because over the past several years we have been able to better define RTS both clinically and molecularly, and because we continue to receive RTS correspondence from around the world, this current protocol is designed to study and answer questions specifically about RTS patients and conditions that result in inherited predisposition to cancer, specifically OS.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 抽象的 已知某些遗传综合征使受影响的患者比一般人群更容易患癌症。罗斯蒙德-汤姆森综合征 (RTS) 是其中一种癌症综合征，特别容易使患者罹患骨肉瘤 (OS)，骨肉瘤是一种发生于儿童和青少年的原发性骨肿瘤。三分之二的 RTS 病例是由 RECQL4 基因突变引起的；然而，对于另外三分之一的患者，基因缺陷尚未被发现。我们有兴趣研究患有 RTS 和相关综合征的患者，以及患有非典型 OS 的患者，以了解 OS 易感性和发病机制的分子机制。这项研究将收集RTS和相关疾病患者及其家庭成员以及可能具有遗传基础的非典型骨肉瘤患者的样本和医疗信息，以便进行分子和遗传学研究，以更好地了解原发综合征（RTS）、癌症发展的倾向以及OS的分子发病机制。 一、假设 在临床和分子水平上研究罕见的癌症易感综合征（RTS）将有助于深入了解普通人群中癌症（OS）的发病机制。 二.具体目标 具体目标 1：收集并分析 RTS 及相关综合征和非典型 OS 患者及其家庭成员的临床样本。样本将包括血液、组织（正常和肿瘤）和体液，这些样本将提供给研究人员进行研究，这将有助于定义和表征导致这些遗传性疾病及其癌症倾向的潜在遗传缺陷。 具体目标 2：收集并分析受 RTS 和相关综合征以及非典型 OS 影响的患者及其家庭成员的医疗记录。临床信息将允许基因型-表型分析与分子研究相结合。 三． 一、背景及意义 RTS是一种遗传性疾病，属于一类家族性癌症易感综合征，包括共济失调毛细血管扩张症、范可尼贫血、色素性干皮病、先天性角化不良、布卢姆综合征和沃纳综合征。患有这些疾病的患者都有已知的遗传缺陷，这些缺陷使他们患某些类型癌症的风险增加。 RTS 患者特别容易发生 OS（一种原发性恶性骨肿瘤）。他们还可能有其他临床特征，如皮肤异色症、身材矮小、骨骼缺陷、头皮毛发、眉毛或睫毛稀疏或缺失、青少年白内障、胃肠道紊乱和牙齿异常。 RTS 的分子基础已为部分患者（约 2/3）所知，并且涉及 RECQL4 基因突变。另外 1/3 患者的分子基础目前尚不清楚，但可能涉及另一个或多个基因的突变（遗传异质性）。 RECQL4蛋白的功能尚不完全清楚，但据信它在DNA复制和维持基因组稳定性中发挥作用。在 RTS 患者中，与没有 RECQL4 突变的 RTS 患者相比，携带 RECQL4 基因截短突变的患者发生 OS 和骨缺陷的风险显着更高。因此，RECQL4 基因途径被认为在 OS 和骨骼发育的发病机制中发挥作用。其他几个基因，包括 p53 和 RB，被认为在散发性 OS 的发病机制中发挥着核心作用，这些基因的结构性突变分别导致 Li-Fraumeni 综合征和遗传性视网膜母细胞瘤。这两种综合征也与 OS 风险增加相关，但两者都不比 RTS 带来更高或更具体的 OS 风险。最近，另外两种综合征，RAPADILINO 综合征和 Baller-Gerold 综合征 (BGS)，在某些情况下也被发现是由 RECQL4 突变引起的；然而，这些综合征的 OS 风险尚未明确。对于 RTS 以及其他家族性癌症易感综合征，需要持续收集和生成临床和分子水平的原始数据，以便了解潜在的分子缺陷和临床后果，特别是与癌症相关的分子缺陷和临床后果。 由于这些疾病在世界范围内都是罕见的，因此积累受影响患者及其亲属的数据以研究他们的遗传物质成为一项艰巨的任务。本研究的目的是收集和分析受 RTS 和相关疾病或不寻常形式的 OS 影响的患者及其家庭成员的临床数据和生物标本。该项目的主要长期目标之一是通过研究 RTS 或其他 RECQL4 疾病患者来进一步了解 OS 的生物学。此前，RTS 患者参加了一项更广泛的研究，题为“家族性癌症易感综合征的分子基础”(H-7207)。因为在过去的几年里，我们已经能够在临床和分子方面更好地定义 RTS，并且因为我们不断收到来自世界各地的 RTS 信件，所以当前的协议旨在研究和回答专门关于 RTS 患者和导致癌症遗传易感性的病症（特别是 OS）的问题。