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: 8938239
• 负责人: MARK H GREENE
• 金额: $ 626.26万
• 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/8938239
• 关键词: Acute Myelocytic Leukemia; Adolescent; Adrenal Gland Cancer; Alleles; American; Aplastic Anemia; Award; BRAF gene; BRCA1 gene; BRCA2 gene; Behavior; Behavioral; Biogenesis; Biological; Biology; Bone Marrow Transplantation; Bone Tissue; CBL gene; CEBPA gene; Cancer-Predisposing Gene; Caring; Cervix Neoplasms; Clinical; Cloning; Collaborations; Collection; Colonic Polyps; Color; Complex; Consent; Costello syndrome; Counseling; DICER1 gene; DNA; Decision Making; Development; Diamond; Diamond-Blackfan anemia; Diethylstilbestrol; Disease; Division of Cancer Epidemiology and Genetics; Dyskeratosis Congenita; Dysmyelopoietic Syndromes; Educational workshop; Eligibility Determination; Embryology; Employee Strikes; Enrollment; Epidemiology; Exposure to; Eye; Family; Family Study; Family member; Fanconi' s Anemia; Fertility; Foundations; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Programming; Genetic Risk; Genetic screening method; Genomics; Germ-Line Mutation; Grant; Gynecologic Oncology Group; Hairy Cell Leukemia; Hamartoma; Hand; Hereditary Breast Carcinoma; Hereditary Breast and Ovarian Cancer Syndrome; Hereditary Malignant Neoplasm; Hereditary Neoplastic Syndromes; Human Genetics; Human Papillomavirus; Inborn Genetic Diseases; Individual; Inherited; International; Investigation; Jaffe-Campanacci syndrome; Juvenile Myelomonocytic Leukemia; Kidney Neoplasms; LIG4 gene; Laboratories; Learning; Li-Fraumeni Syndrome; Lymphoma; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of ovary; Malignant neoplasm of testis; Malignant neoplasm of urinary bladder; Manuscripts; Maps; MicroRNAs; Modality; Modeling; Moods; Mutation; Myotonic Dystrophy; NF1 gene; Neoplasms; Neurofibromatosis 1; Neutropenia; Noonan Syndrome; Nose; Operative Surgical Procedures; Pancytopenia; Pathogenesis; Pathogenicity; Pathway Analysis; Patients; Peer Review; Penetrance; Perinatal Exposure; Persons; Phenotype; Pituitary Neoplasms; Play; Pleuropulmonary Blastoma; Plexiform Neurofibroma; Predisposition; Preparation; Protocols documentation; Publications; Publishing; Radial; Radiation; Registries; Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Resources; Risk; Risk Reduction; Role; Sampling; Screening for cancer; Signal Transduction; Site; Social Network; Solid Neoplasm; Susceptibility Gene; Syndrome; TINF2 gene; TP53 gene; Test Result; Testing; Thrombocytopenia; Thyroid Gland; Time; Tissue Banks; Training; Translational Research; United States National Institutes of Health; Variant; Writing; base; bench to bedside; cancer genetics; cancer genomics; cancer prevention; cancer risk; clinical phenotype; cohort; developmental disease; early onset; epidemiologic data; exome sequencing; genetic risk assessment; genetic variant; genome wide association study; high risk; immune function; in vitro Assay; kindred; malignant breast neoplasm; member; meningioma; multidisciplinary; mutation carrier; neuropsychiatry; next generation; next generation sequencing; novel; osteosarcoma; patient advocacy group; phosphodiesterase 11a; prospective; psychosocial; sarcoma; screening; soft tissue; telomere; tool; tumorigenesis

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 study has ended, but its biospecimens continue to be used in multiple translational research projects. To date, 17 clinical manuscripts have been published and 32 reports plus 7 manuscripts under review (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 which include high risk of aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and selected solid tumors. We have enrolled 1722 members from 406 IBMFS 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 syndromes, and identifying very short telomeres as pathognomonic for DC. Under a Fanconi Anemia Research Foundation grant, we are writing a report on immune function in FA patients. We collaborated on development of an in vitro assay for pathogenicity of missense variants of unknown significance in FANCD1/BRCA2. We have identified four (TINF2, WRAP53, fTEL1, ACD) of the 10 known dyskeratosis congenita genes, and provided the first evidence that the DC phenotype includes a high risk of neuropsychiatric disorders. 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. 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 725 consented members from 142 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 published multiple FTGCT-related analyses related with the International Testicular Cancer Linkage Consortium. It has ceased to function, (having been replaced by the Testicular Cancer Association Consortium, TECAC) but it yielded the key hypothesis that has catalyzed current research into testicular cancer genomics, i.e., that the underlying genetic susceptibility involves the combined effects of multiple common genetic variants, each of relatively weak effect. 30 variants in 18 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, found no evidence of a dysmorphic phenotype, described an association between in utero exposure to diethylstilbestrol and FTGCT, determined that FTGCT is a site-specific cancer syndrome, and presented the first prospective FTGCT risk analysis, which revealed a 12-fold increase in TGCT risk among high-risk family members. The 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. We have initiated a new LFS study which has enrolled 455 members (50 of whom have elected the MRI screening protocol) from 142 new families, and is providing genetic counseling and testing in search of new LFS genes in the 30% of LFS patients with a TP53 mutation, investigating novel cancer screening modalities (e.g., total body MRI), attempting to identify genetic modifiers of risk, and studying cancer risk-reduction strategies. We published the proceedings of an international workshop (November 2010) that 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. To date, we have enrolled 339 members from 65 PPB families, evaluated 116 subjects at the NIH Clinical Center and performed DICER1 mutation testing on 150 subjects. Leveraging an NIH Bench-to-Bedside award, we have formed a collaboration with the research group which discovered DICER1, with whom we are doing a detailed clinical phenotype and cancer risk quantification study of this rare, novel syndrome. A review of the PPB syndrome was published online in GeneReviews, and a report describing PPB-related nasal chondromesenchymal hamartoma is in press. Publications describing 350 registry-based PPB cases, the first 25 PPB families evaluated, and an analysis of PPB-related thyroid neoplasia are in preparation Neurofibromatosis 1 is a classic hereditary cancer susceptibility disorder. We are further defining its phenotype and seeking genetic modifiers of NF1 penetrance. We have shown that Jaffe-Campanacci syndrome is allelic to NF1. We have identified specific genetic variants that modify the risk of developing NF1-related caf-au-lait macules, an important proof-of-principle observation, and demonstrated that loss of the wild-type NF1 allele is the primary driver of plexiform neurofibroma tumorigenesis.Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer is a vital component of each study in CGB's research portfolio, which has yielded more than 50 peer-reviewed publications. We have extended the application of a new genetic counseling tools, e.g., the Colored Ecogenetics Relationship Map, from HBOC to FTGCT, applied novel analytic strategies, such as social network analysis, analyzed the variables associated with choosing surgery or screening in GOG-199, assessed determinants of bone marrow transplant decision-making within FA families, and explored the impact of ambiguous and false-positive screening test results on mood and screening behavior of BRCA1/2 mutation carriers. In our Rare Familial Cancer Syndromes WES sequencing project, we have etiologically implicated CBL mutations in juvenile JMML, CEBPA in familial AML, and BRAF mutations in familial hairy cell leukemia. We have also shown that Dubowitz syndrome is a syndrome complex of multiple genetically-distinct, phenotypically overlapping disorders in which germline LIG4 mutations play an etiologic role.

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。与本研究相关的临床活动已经结束，但其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，32篇报告和7篇正在审查的论文（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）及相关疾病，包括再生障碍性贫血、骨髓增生异常综合征（MDS）、急性髓性白血病（AML）和特定实体瘤。我们招收了来自406个IBMFS家庭的1722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，扩大这些综合征的临床表型，并确定非常短的端粒是DC的病理特征。在范可尼贫血研究基金会的资助下，我们正在撰写一篇关于FA患者免疫功能的报告。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。我们已经鉴定了10个已知角化异常先天性基因中的4个（TINF2, WRAP53, fTEL1， ACD），并首次提供了DC表型包括神经精神疾病高风险的证据。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。家族性睾丸癌是一种研究不充分的家族性癌症疾病，目前有两种方案进行评估，一种是建立新的多病例家族，另一种旨在定位和克隆新的TGCT易感基因。通过前者，我们从142个新确定的家庭中招募了725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。我们发表了多个与国际睾丸癌连锁联盟相关的ftgct相关分析。它已经停止了作用（被睾丸癌协会联盟（TECAC）所取代），但它产生了催化当前睾丸癌基因组学研究的关键假设，即潜在的遗传易感性涉及多个常见遗传变异的综合作用，每个变异的作用相对较弱。现已发现18个基因组区域（涉及睾丸胚胎学、生育学、KIT信号传导、端粒生物学）的30个变异与TGCT的遗传发病机制有关。我们参与了最近的两项新的GWAS分析，确定了5个相关的基因组区域，没有发现畸形表型的证据，描述了子宫内暴露于二乙基烯雌酚和FTGCT之间的关联，确定了FTGCT是一种位点特异性癌症综合征，并提出了第一个前瞻性FTGCT风险分析，结果显示高危家庭成员中TGCT风险增加了12倍。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。我们已经启动了一项新的LFS研究，从142个新家庭中招募了455名成员（其中50人选择了MRI筛查方案），并提供遗传咨询和测试，以在30%的TP53突变的LFS患者中寻找新的LFS基因，研究新的癌症筛查方式（如全身MRI），试图识别风险的遗传修饰因子，并研究癌症风险降低策略。我们发表了一个国际研讨会（2010年11月）的会议记录，结果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。到目前为止，我们已经从65个PPB家族中招募了339名成员，在NIH临床中心评估了116名受试者，并对150名受试者进行了DICER1突变检测。利用美国国立卫生研究院从实验室到床边的奖励，我们与发现DICER1的研究小组建立了合作关系，我们正在对这种罕见的新型综合征进行详细的临床表型和癌症风险量化研究。一篇关于PPB综合征的综述发表在GeneReviews网站上，一篇描述PPB相关鼻腔软骨间充质错构瘤的报告正在出版中。文献描述了350例基于登记的PPB病例，前25个PPB家族的评估，以及PPB相关甲状腺瘤变的分析正在准备中。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。我们已经证明Jaffe-Campanacci综合征是NF1的等位基因。我们已经确定了特定的遗传变异，可以改变NF1相关的cafalait斑疹的发生风险，这是一个重要的原理证明观察，并证明野生型NF1等位基因的缺失是丛状神经纤维瘤发生的主要驱动因素。家族性癌症的遗传咨询、社会心理和行为研究是CGB研究组合中每项研究的重要组成部分，已发表50多篇同行评审出版物。我们扩展了新的遗传咨询工具的应用，如彩色生态遗传学关系图，从HBOC到FTGCT，应用了新的分析策略，如社会网络分析，分析了GOG-199中选择手术或筛查的相关变量，评估了FA家族中骨髓移植决策的决定因素。探讨模棱两可和假阳性筛选试验结果对BRCA1/2突变携带者情绪和筛查行为的影响。在我们的罕见家族性癌症综合征WES测序项目中，我们在病因学上发现，CBL突变与青少年JMML有关，CEBPA突变与家族性AML有关，BRAF突变与家族性毛细胞白血病有关。我们还表明，Dubowitz综合征是多种遗传上不同，表型上重叠的疾病的综合征复合物，其中种系LIG4突变在病因学上起作用。