Clinical Genetic Studies of Familial and Hereditary Cancer Syndromes

家族性和遗传性癌症综合征的临床遗传学研究

• 批准号: 8763619
• 负责人: MARK H GREENE
• 金额: $ 515.52万
• 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/8763619
• 关键词: Acute Myelocytic Leukemia; Adrenal Gland Cancer; Affect; American; Aplastic Anemia; Award; BRCA1 gene; BRCA2 gene; Behavior; Behavioral; Biogenesis; Biological; Biology; Bone Marrow Transplantation; Bone Tissue; Cancer-Predisposing Gene; Caring; Cervical; Clinical; Cloning; Collaborations; Colonic Polyps; Color; Consent; Costello syndrome; DICER1 gene; DNA; Data; Decision Making; Development; Diamond; Diamond-Blackfan anemia; Disease; Division of Cancer Epidemiology and Genetics; Dyskeratosis Congenita; Dysmyelopoietic Syndromes; Educational workshop; Embryology; Employee Strikes; Enrollment; Epidemiology; Eye; Family; Family Study; Fanconi' s Anemia; Fertility; Foundations; Genes; Genetic; Genetic Counseling; Genetic Models; Genetic Predisposition to Disease; Genetic screening method; Genomics; Germ-Line Mutation; German population; Grant; Gynecologic Oncology Group; Hand; Hereditary Breast Carcinoma; Hereditary Breast and Ovarian Cancer Syndrome; Hereditary Malignant Neoplasm; Hereditary Neoplastic Syndromes; Human Papillomavirus; Inborn Genetic Diseases; Individual; Inherited; Institutional Review Boards; International; Investigation; Kidney Neoplasms; Laboratories; Learning; Li-Fraumeni Syndrome; Lymphoma; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of ovary; Malignant neoplasm of testis; Manuscripts; Maps; MicroRNAs; Modality; Modeling; Moods; Mutation; Myotonic Dystrophy; NF1 gene; Neoplasms; Neurofibromatosis 1; Neutropenia; Noonan Syndrome; Operative Surgical Procedures; Pancytopenia; Pathogenesis; Pathogenicity; Pathway Analysis; Patients; Peer Review; Penetrance; Phenotype; Pituitary Neoplasms; Pleuropulmonary Blastoma; Predisposition; Protocols documentation; Publications; Publishing; Radial; Rare Diseases; Registries; Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Resources; Risk; Risk Reduction; Role; Sampling; Screening for cancer; Series; Signal Transduction; Social Network; Solid Neoplasm; Susceptibility Gene; Syndrome; TP53 gene; Technology; Test Result; Thrombocytopenia; Time; Tissue Banks; Training; Translational Research; United States National Institutes of Health; Variant; base; bench to bedside; cancer genetics; cancer genomics; cancer prevention; cancer risk; clinical phenotype; cohort; developmental disease; early onset; epidemiologic data; genetic variant; genome wide association study; high risk; immune function; in vitro Assay; kindred; malignant breast neoplasm; member; multidisciplinary; mutation carrier; next generation; novel; osteosarcoma; patient advocacy group; phosphodiesterase 11a; prospective; psychosocial; research clinical testing; sarcoma; screening; soft tissue; telomere; tool

The Clinical Genetics Branch (CGB) is NCI's base for intramural clinical cancer genetics translational research activity. CGB brings a multidisciplinary, epidemiologic perspective to: Understanding the role of genes in the cause, treatment, and prevention of cancer; Developing comprehensive management strategies for high-risk individuals and families; and Training the next generation of clinical cancer genetics investigators.Hereditary Breast/Ovarian Cancer (HBOC) is based on a prospective cohort of 33 BRCA mutation-positive families with extensive clinical/epidemiologic data and biological samples. Clinical activity related to this historic cohort has ended, but the biospecimens collected continue to be used in multiple translational research projects. To date, 17 clinical manuscripts have been published and 31 reports (in collaboration with the international consortium CIMBA) elucidating genetic modifiers of BRCA-related breast and ovarian cancer penetrance have been published. Inherited Bone Marrow Failure Syndromes (IBMFS) Study targets Fanconi anemia (FA) and related disorders with a predilection for aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and selected solid tumors. This is the first epidemiologically-grounded, etiologically-focused investigation of these rare disorders. We enrolled 1610 members from 374 families. Major findings include quantitative estimates of FA- and dyskeratosis congenita (DC)-related cancer risks, identifying the striking similarity in cancer risks in these 2 disorders, expanding the clinical phenotype of these disorders, and identifying very short telomeres as pathognomonic for DC. Under a grant from the Fanconi Anemia Research Foundation, we are studying immune function in FA patients. We have collaboratively analyzed cancer risks in the the North American, German and Israeli FA cohorts, and reported similar data from the NCI cohort. We collaborated on development of an in vitro assay for pathogenicity of missense variants of unknown significance in FANCD1/BRCA2. We have analyzed the North American Diamond- Blackfan Registry (DBAR) and documented for the first time significant risks of cancer, particularly osteogenic sarcoma, in DBA. A closely-related project, Familial Testicular Cancer is an inadequately-studied familial cancer disorder being evaluated under 2 protocols, one accruing new multiple-case families, the other aimed at mapping and cloning new TGCT susceptibility genes. Through the former, we have enrolled 1140 consented members from 144 newly-ascertained families. This multidisciplinary, etiologically-oriented family study has found that testicular microlithiasis is more common than expected in TGCT kindred, recognized a possible new FTGCT syndrome characterized by renal and pituitary neoplasms, colonic polyps, lymphomas and lentigenes, and identified germline mutations in the PDE11A gene as a modifier of FTGCT risk. We were the second largest contributor to International Testicular Cancer Linkage Consortium, through which we published multiple analyses related to the FTGCT phenotype. That Consortium has ceased to function, but it yielded the key hypothesis that has catalyzed current research into testicular cancer genomics, i.e., that the underlying genetic model involves the combined effects of multiple common genetic variants, each of relatively weak effect. Twenty-six variants in 9 genomic regions (involving testicular embryology, fertility,KIT signaling, telomere biology) have now been implicated in the genetic pathogenesis of TGCT. We contributed to two new recent GWAS analyses which identified 5 of the implicated genomic regions. BRThe Li-Fraumeni Syndrome (LFS), originally identified by DCEG investigators 40 years ago is a rare, inherited disorder caused by germline TP53 mutations, with increased risks of early-onset bone and soft tissue sarcomas, breast, adrenal and brain cancer. After a long hiatus, we have initiated a new LFSstudy which will conduct comprehensive clinical evaluations, provide genetic counseling and testing, investigate cancer screening modalities, identify genetic modifiers, study cancer risk-reduction strategies, and search for the genetic etiology in the 30% of affected patients without a TP53 mutation. An international workshop was held in November 2010 and resulted in formation of a new international LFS research consortium and the first LFS patient advocacy group. Familial Pleuropulmonary Blastoma (PPB) is a newly-described syndrome caused by germline mutations in DICER1; it represents the first known cancer predisposition syndrome caused by altered microRNA biogenesis. Leveraging an NIH Bench-to-Bedside award, we have formed a collaboration with the research group which made this remarkable observation, as a means to engage in the cutting-edge domain of miRNA research and introduce this technology into DCEG's research armamentarium. We will focus on more precisely defining the clinical phenotype of this remarkable disorder, in a new project that has just been submitted for IRB review. Neurofibromatosis 1 is a classic hereditary cancer susceptibility disorder. We are further defining its phenotype and seeking genetic modifiers of NF1 penetrance. Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer is a vital component of CGB's research portfolio, which has yielded nearly 50 peer-reviewed publications. A series of projects are actively underway as part of each familial cancer study being conducted by the Branch. We are developing new genetic counseling tools (e.g., the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of BRCA1/2 mutation carriers.g., the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of BRCA1/2 mutation carriers.

临床遗传学分部（CGB）是NCI内部临床癌症遗传学转化研究活动的基地。CGB从多学科、流行病学的角度来理解基因在癌症的起因、治疗和预防中的作用；为高危个人和家庭制定综合管理战略；培训下一代临床癌症遗传学研究人员。遗传性乳腺癌/卵巢癌（HBOC）是基于33个BRCA突变阳性家庭的前瞻性队列研究，具有广泛的临床/流行病学数据和生物样本。与这一历史性队列相关的临床活动已经结束，但收集的生物标本继续用于多个转化研究项目。迄今为止，已经发表了17篇临床论文和31篇报告（与国际联盟CIMBA合作），阐明了brca相关乳腺癌和卵巢癌外显率的遗传修饰因子。遗传性骨髓衰竭综合征（IBMFS）研究针对范可尼贫血（FA）和相关疾病，偏爱再生障碍性贫血、骨髓增生异常综合征（MDS）、急性髓性白血病（AML）和选定的实体肿瘤。这是第一次以流行病学为基础，以病因学为重点的对这些罕见疾病的调查。我们招募了来自374个家庭的1610名成员。主要发现包括定量估计FA-和先天性角化不良（DC）相关的癌症风险，确定这两种疾病的癌症风险惊人的相似性，扩大这些疾病的临床表型，并确定非常短的端粒是DC的病理特征。在Fanconi贫血研究基金会的资助下，我们正在研究FA患者的免疫功能。我们合作分析了北美、德国和以色列FA队列的癌症风险，并报告了NCI队列的类似数据。我们合作开发了FANCD1/BRCA2中未知意义错义变异致病性的体外检测。我们分析了北美Diamond- Blackfan Registry (DBAR)，首次记录了DBA患癌症的显著风险，特别是成骨肉瘤。家族性睾丸癌是一个密切相关的项目，是一种研究不足的家族性癌症疾病，目前有两种方案进行评估，一种方案建立新的多病例家族，另一种方案旨在定位和克隆新的TGCT易感基因。通过前者，我们从144个新确定的家庭中招募了1140名同意的成员。这项多学科、以病因学为导向的家族研究发现，睾丸微石症在TGCT家族中比预期的更常见，认识到一种可能的新型FTGCT综合征，其特征是肾脏和垂体肿瘤、结肠息肉、淋巴瘤和慢基因，并发现PDE11A基因的种系突变是FTGCT风险的一个修饰因子。我们是国际睾丸癌连锁联盟的第二大贡献者，通过该联盟，我们发表了与FTGCT表型相关的多项分析。该联盟已经停止运作，但它产生了催化当前睾丸癌基因组学研究的关键假设，即潜在的遗传模型涉及多个常见遗传变异的综合影响，每个变异的影响相对较弱。现已发现9个基因组区域的26个变异（涉及睾丸胚胎学、生育学、KIT信号传导、端粒生物学）与TGCT的遗传发病机制有关。我们贡献了最近的两个新的GWAS分析，确定了5个相关的基因组区域。Li-Fraumeni综合征（LFS）最初由DCEG研究人员在40年前发现，是一种罕见的遗传性疾病，由种系TP53突变引起，具有早发性骨和软组织肉瘤、乳腺癌、肾上腺癌和脑癌的风险增加。经过长时间的中断，我们启动了一项新的lfs研究，该研究将进行全面的临床评估，提供遗传咨询和检测，研究癌症筛查方式，识别遗传修饰剂，研究癌症风险降低策略，并在30%没有TP53突变的受影响患者中寻找遗传病因。2010年11月举行了一次国际研讨会，形成了一个新的国际LFS研究联盟和第一个LFS患者倡导小组。家族性胸膜肺母细胞瘤（PPB）是由DICER1基因种系突变引起的一种新发现的综合征；它代表了已知的第一个由微小rna生物发生改变引起的癌症易感性综合征。利用美国国立卫生研究院从实验室到床边的奖励，我们已经与研究小组形成了合作，该小组做出了这一非凡的观察，作为参与miRNA研究的前沿领域的一种手段，并将这项技术引入DCEG的研究设备。我们将专注于更精确地定义这种显著疾病的临床表型，在一个刚刚提交给IRB审查的新项目中。神经纤维瘤病是一种典型的遗传性癌症易感性疾病。我们正在进一步确定其表型并寻找NF1外显率的遗传修饰因子。家族性癌症的遗传咨询、社会心理和行为研究是CGB研究组合的重要组成部分，已经发表了近50篇同行评审的出版物。作为该科正在进行的每项家族性癌症研究的一部分，一系列项目正在积极进行。我们正在开发新的遗传咨询工具（如有色生态遗传学关系图），应用新的分析策略，如社会网络分析，分析与GOG-199中选择手术或筛查相关的变量，评估FA家族中骨髓移植决策的决定因素，并探索模棱两可的筛查测试结果对BRCA1/2突变携带者的情绪和筛查行为的影响。应用新的分析策略，如社会网络分析，分析与GOG-199中选择手术或筛查相关的变量，评估FA家族中骨髓移植决策的决定因素，并探索模棱两可的筛查测试结果对BRCA1/2突变携带者情绪和筛查行为的影响。