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; 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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 抽象的 已知某些遗传综合征比普通人群更容易影响癌症。 Rothmund-Thomson综合征（RTS）是这些癌症综合征之一，特别使患者患有骨肉瘤（OS），骨肉瘤（OS）是一种发生在儿童和青少年中的原发性骨肿瘤。称为RECQL4的基因中的突变占RT病例的三分之二；但是，对于其他三分之一的患者，尚未发现基因缺陷。我们有兴趣研究RT和相关综合征的患者以及具有非典型OS的患者，以了解OS易感性和发病机理的分子机制。这项研究将允许收集RTS和相关疾病患者及其家人的样本和医疗信息，以及可能具有遗传基础的非典型骨肉瘤患者，以便可以更好地了解分子和遗传研究以更好地了解原发性综合征（RTS），以及对癌症发育的倾向，以及对癌症的倾向，以及分子的倾向。 I.假设 在临床和分子水平上研究罕见的癌症易感综合征（RTS）将为一般人群中癌症（OS）的发病机理提供见解。 ii。具体目标 具体目标1：收集和分析受RT和相关综合征和非典型OS及其家人的非典型综合征和非典型形式的患者的临床样本。样品将包括血液，组织（正常和肿瘤）以及人体液体，这些样品将为研究人员提供，以进行研究，这将有助于定义和表征导致这些遗传疾病及其癌症倾向的潜在遗传缺陷。 具体目标2：收集和分析患有RTS及其相关综合症和非典型OS及其家人的患者的病历。临床信息将允许基因型 - 表型分析与分子研究结合使用。 iii。 背景和意义 RTS是一种遗传疾病，属于一类家族性癌症易感性综合征，包括共济失调 - 链抗血管菌，fanconi贫血，静脉疾病，色素色素，性疾病性康涅狄格州，布鲁姆综合征和werner综合征。这些疾病的患者均具有已知的遗传缺陷，使他们对某些类型的癌症的风险增加。 RTS患者特别容易发生OS，这是原发性恶性骨肿瘤。他们还可能具有其他临床特征，例如poikilederma，小地位，骨骼缺陷，稀疏或没有头皮头发，眉毛或睫毛，少年白内障，胃肠道障碍和牙齿异常。 RT的分子基础以患者的子群（约2/3）而闻名，并涉及RECQL4基因的突变。目前尚不清楚其他1/3患者的分子基础，但可能涉及另一个基因或基因的突变（遗传异质性）。 RECQL4蛋白的功能尚未完全了解，但据信它在DNA复制和维持基因组稳定性中起作用。在RTS患者中，与没有RECQL4突变的RTS患者相比，RECQL4基因中持续突变的患者的患有OS和骨缺损的风险明显更高。因此，RECQL4基因途径被认为是在OS的发病机理和骨骼发育的发病机理中发挥作用。人们认为包括p53和RB在内的其他几个基因在零星OS的发病机理中起着核心作用，这些基因的宪法突变分别负责Li-Fraumeni综合征和遗传性视网膜母细胞瘤。这两种综合症都与OS的风险增加有关，但与RT相比，OS的风险更高或更具体。最近，在某些情况下，RECQL4中的突变引起了其他两种综合征，即Rapadilino综合征和Baller-Gerold综合征（BGS）。但是，尚未定义这些综合症中OS的风险。对于RT以及其他家族性癌症易感综合征，持续需要在临床和分子水平上收集和生成主要数据，以了解基本的分子缺陷，尤其是在与癌症有关的临床后果。 由于这些是全球罕见的疾病，因此积累了受影响的患者及其亲戚的数据以研究其遗传物质成为一项艰巨的任务。这项研究的目的是收集和分析受RTS和相关疾病或异常形式的OS及其家人的患者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疾病的患者进一步了解OS的生物学。以前，RT患者接受了一项更广泛的研究，该研究为家族性癌症易感综合征的分子基础（H-7207）。因为在过去的几年中，我们能够在临床和分子上更好地定义RT，并且由于我们继续接收来自世界各地的RTS信函，因此该当前方案旨在研究和回答有关RTS患者和条件的问题，并导致遗传易经性癌症，特别是OS。