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: 8349569
• 负责人: MARK H GREENE
• 金额: $ 399.76万
• 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/8349569
• 关键词: Acute Myelocytic Leukemia; Adrenal Gland Cancer; Advocacy; Affect; Age; American; Aplastic Anemia; Award; BAK1 gene; BRCA1 gene; BRCA2 gene; Behavior; Behavioral; Biogenesis; Biological; Bone Marrow Transplantation; Bone Tissue; Cancer Family; Cancer-Predisposing Gene; Candidate Disease Gene; Caring; Cervical; Clinical; Cloning; Collaborations; Collection; Colonic Polyps; Color; Communities; Consent; Costello syndrome; Counseling; DICER1 gene; DNA; Data; Decision Making; Development; Diamond; Diamond-Blackfan anemia; Disease; Dissection; Division of Cancer Epidemiology and Genetics; Dyskeratosis Congenita; Dysmyelopoietic Syndromes; Educational workshop; Employee Strikes; Enrollment; Epidemiology; Epithelial Cells; Eye; Family; Family Study; Family member; Fanconi' s Anemia; Foundations; General Population; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic screening method; Genomics; Germ-Line Mutation; German population; Grant; Gynecologic Oncology Group; HRAS gene; Hand; Hereditary Breast Carcinoma; Hereditary Breast and Ovarian Cancer Syndrome; Hereditary Malignant Neoplasm; Hereditary Neoplastic Syndromes; Histopathology; Hormones; Human; Human Papillomavirus; Inborn Genetic Diseases; Individual; Inherited; Institutional Review Boards; International; Investigation; KITLG gene; KRAS2 gene; Kidney Neoplasms; Laboratories; Lead; Learning; Li-Fraumeni Syndrome; Lymphoma; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of ovary; Malignant neoplasm of testis; Maps; Methods; MicroRNAs; Modality; Modeling; Moods; Multiple Hamartoma Syndrome; Mutate; Mutation; Myotonic Dystrophy; Neoplasms; Neurofibromatosis 1; Neutropenia; Noonan Syndrome; Oncogenes; Operative Surgical Procedures; Ovarian; PTEN gene; Pancytopenia; Pathogenicity; Pathway Analysis; Patients; Peer Review; Penetrance; Phenotype; Pituitary Neoplasms; Pleuropulmonary Blastoma; Population; Predisposition; Protocols documentation; Publications; Publishing; Radial; Rare Diseases; Registries; Reporting; Research; Research Activity; Research Personnel; Resources; Risk; Risk Reduction; Role; Sampling; Schedule; Screening for cancer; Screening procedure; Series; Social Network; Solid Neoplasm; Staging; Surface; Susceptibility Gene; Syndrome; TP53 gene; Technology; Test Result; Thrombocytopenia; Time; Tissue Banks; Training; Translational Research; Tumor Suppressor Genes; Tumor Tissue; United States National Institutes of Health; Variant; anticancer research; base; bench to bedside; cancer diagnosis; cancer genetics; cancer prevention; cancer risk; clinical phenotype; cohort; developmental disease; early experience; early onset; epidemiologic data; epidemiology study; follow-up; genetic analysis; genetic epidemiology; genetic risk assessment; genome wide association study; high risk; immune function; in vitro Assay; in vivo; kindred; malignant breast neoplasm; member; multidisciplinary; mutation carrier; next generation; novel; osteosarcoma; phosphodiesterase 11a; prospective; psychosocial; reproductive epidemiology; research clinical testing; sarcoma; 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) [CAS 8040] is based on a prospective cohort of 33 BRCA mutation-positive families with extensive clinical/epidemiologic data and biological samples [NCI Protocol #02-C-0212]. Research highlights include a series of important positive, and definitive-negative candidate gene studies analyzing genetic modifiers of BRCA1/2-related breast cancer risk as part of the Consortium of Investigators of Modifiers of BRCA1 (CIMBA) project, and a series of counseling/psychosocial reports of our early experience with HBOC families undergoing genetic risk assessment. With a mean prospective follow-up of 17.7 years for 395 mutation-negative family members, we observed no excess breast cancer risk compared with the general population. We are developing new laparoscopic tissue collection methods for in vivo collection of human ovarian surface epithelial cells for translational research purposes [CAS 10376], with very promising ovarian epithelial cell yields. Inherited Bone Marrow Failure Syndromes (IBMFS) Study [CAS 7130] 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 1400 members from 350 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 [CAS 10475]. 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, Cancer in Rare Developmental Disorders [CAS 10549] is in its early stages of development. It leverages the observation that some oncogenes and tumor suppressor genes that are somatically altered in tumor tissue have also been found to be mutated in the germline of individuals with inherited conditions, e.g. Noonan (KRAS), Costello (HRAS) and Cowden syndromes (PTEN). Interdisciplinary dissection of such rare associations may lead to the focused identification of novel cancer genes. Thus, we will study rare developmental syndromes that are associated with cancer. Familial Testicular Cancer [CAS 7070, 7130] is an inadequately-studied familial cancer disorder being evaluated under 2 protocols, one accruing new multiple-case families [NCI Protocol #02-C-0178], the other aimed at mapping and cloning new TGCT susceptibility genes [NCI Protocol #04-C-N076]. Through the former, we have enrolled 609 consented members from 119 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 modifier of FTGCT risk. We are the second largest contributor to International Testicular Cancer Linkage Consortium, through which we published a descriptive analysis of 469 TGCT families (containing 1002 TGCT cases), and documented that age-at-cancer-diagnosis is significantly younger in familial versus sporadic TGCT. Analyses of the histopathology of familial versus sporadic TGCT, and quantification of the risk of cancers other than TGCT in multiple-case families are nearing completion. As part of DCEGs Rare Cancers iSELECT project, we have confirmed strong associations between familial TGCT risk and 4 genomic regions recently implicated in GWAS analyses, i.e., KITLG, BAK1, DMRT1, and TERT-CLPTM1L. A family-based familial TGCT GWAS is under analysis, with a special focus on copy number variants. These data are also being pooled with those from a sporadic TGCT GWAS currently under analysis by colleagues in the Hormone and Reproductive Epidemiology Branch, DCEG. BR> The Li-Fraumeni Syndrome (LFS) [CAS 10503], 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 LFS study 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 is scheduled for November 2010, to launch the activities of a newly-formed consortium for the study of LFS, and to mobilize the LFS advocacy community. Familial Pleuropulmonary Blastoma (PPB) [CAS 10548] 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 [CAS 10567] 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 more than 30 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.

临床遗传学分支（CGB）是NCI的壁内临床癌症​​遗传学转化研究活动的基础。 CGB带来了多学科的流行病学观点：了解基因在癌症原因，治疗和预防中的作用；为高危个人和家庭制定全面的管理策略；并培训下一代临床癌症遗传学研究者。遗传性乳腺/卵巢癌（HBOC）[CAS 8040]基于33个BRCA突变阳性家族的前瞻性队列，具有广泛的临床/流行病学数据和生物样品[NCI协议＃02-C-0212]。研究重点包括一系列重要的阳性和确定性的候选基因研究，分析了BRCA1/2相关乳腺癌风险的遗传修饰符，这是BRCA1（CIMBA）项目研究人员联盟（CIMBA）项目的一部分，以及我们对HBOC家族的早期咨询/心理社会报告的研究，对HBOC家庭进行了遗传风险评估。 395个突变阴性家庭成员的平均前瞻性随访为17。7年，与普通人群相比，我们没有观察到过多的乳腺癌风险。我们正在开发新的腹腔镜组织收集方法，用于在体内收集人卵巢表面上皮细胞，以用于转化研究目的[CAS 10376]，具有非常有希望的卵巢上皮细胞的产量。遗传的骨髓衰竭综合征（IBMFS）研究[CAS 7130]靶向fanconi贫血（FA）和相关疾病，具有偏爱性障碍性障碍性障碍性障碍，骨髓增生型综合征（MDS），急性髓样白血病（AML）（AML）和选定的实体滴滴。这是对这些罕见疾病的第一个流行病学基础，以病因为中心的研究。我们招募了来自350个家庭的1400名成员。主要发现包括对FA-和异常症状的康格诺塔（DC）相关的癌症风险的定量估计，确定这两种疾病中癌症风险的惊人相似性，扩大这些疾病的临床表型，并确定非常短的远程触点是DC的病理。根据Fanconi贫血研究基金会的赠款，我们正在研究FA患者的免疫功能[CAS 10475]。我们已经在北美，德国和以色列足总队列中协作分析了癌症风险，并报告了NCI队列的类似数据。我们合作开发了一种在FANCD1/BRCA2中具有未知意义的错义变体的致病性。我们已经分析了北美钻石登记册（DBAR），并在DBA首次记录了癌症，尤其是成骨的肉瘤的重大风险。一个密切相关的项目，罕见发育障碍的癌症[CAS 10549]正处于发展的早期阶段。它利用了这样的观察结果，即在具有遗传条件的个体的种系中，还发现某些在肿瘤组织中在肿瘤组织中发生符号改变的肿瘤基因和肿瘤抑制基因，例如Noonan（Kras），Costello（Hras）和Cowden综合征（PTEN）。这种罕见关联的跨学科解剖可能会导致对新型癌症基因的重点鉴定。因此，我们将研究与癌症相关的罕见发育综合征。家族性睾丸癌[CAS 7070，7130]是一种未充分研究的家族性癌症障碍，根据2个方案进行了评估，一种是一种新的多案例家族[NCI协议＃02-C-0178]，另一种旨在映射和克隆新的TGCT易感基因[NCI协议＃04-C-N076]。通过前者，我们已经招募了来自119个新范围家庭的609名同意成员。这项多学科，病因为导向的家庭研究发现，睾丸微石质症在TGCT中比预期的，在TGCT中预期的是一种可能的新FTGCT综合征，其特征是肾脏和垂体肿瘤，结肠息肉，淋巴瘤，淋巴瘤，淋巴瘤和弯腰元素和lestifiped Germline Intgative in ftg sodct sodct sodct sodct aSee11a aSee11a aSee11a Asee as aSee11a Asee11a sodectif。我们是国际睾丸癌连接联盟的第二大贡献者，通过该财团，我们对469个TGCT家族（包含1002个TGCT病例）进行了描述性分析，并记录了家族性与零星TGCT的年龄较大的诊断。家族性TGCT的组织病理学组织病理学的分析，以及多盘家族中TGCT以外的癌症风险的量化正在接近完成。作为DCEG稀有癌症项目的一部分，我们已经证实了家族性TGCT风险与最近与GWAS分析有关的4个基因组区域之间的密切关联，即Kitlg，Bak1，dmrt1和Tert-Clptm1l。基于家庭的家族性TGCT GWAS正在分析中，特别关注拷贝数变体。这些数据还与来自激素和生殖流行病学分支的同事目前正在分析的零星TGCT GWA的数据合并。 Br> Li-Fraumeni综合征（LFS）[CAS 10503]，最初由DCEG研究者确定40年前是一种罕见的，是由生殖线TP53突变引起的一种罕见的遗传性疾病，其早期骨骼和软组织肉瘤，乳腺癌，乳腺癌，肾上腺，肾上腺和脑癌的风险增加。经过长时间的休假后，我们开始了一项新的LFS研究，该研究将进行全面的临床评估，提供遗传咨询和测试，研究癌症筛查方式，识别遗传修饰符，研究癌症风险减少策略，并在没有ATP53突变的患者中寻找30％的患者中的遗传病因。计划于2010年11月举行的国际研讨会，启动了一个新成立的LFS研究的活动，并动员LFS倡导社区。家族性胸膜肺泡（PPB）[CAS 10548]是由DICER1种系突变引起的一种新描述的综合征。它代表了由microRNA生物发生变化引起的第一个已知的癌症易感综合征。我们利用NIH基准奖奖，我们与研究小组建立了合作，这使这一非凡的观察结果是参与Mirna Research的尖端领域的手段，并将这项技术引入DCEG的DCEG研究Armamentarium。在一个刚刚提交IRB审查的新项目中，我们将重点放在更精确地定义这种非凡疾病的临床表型。神经纤维瘤病1 [CAS 10567]是一种经典的遗传癌敏感性障碍。我们正在进一步定义其表型并寻求NF1渗透的遗传修饰剂。家族癌症中的遗传咨询，社会心理和行为研究是CGB研究组合的重要组成部分，该组合已经产生了30多个同行评审的出版物。作为分支机构进行的每项家族癌症研究的一部分，积极进行了一系列项目。 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有色生态估计关系图），应用新颖的分析策略，例如社交网络分析，分析与选择手术或筛查有关的GOG-199中的变量，评估FA家族中骨髓移植决策的决定因素，以及探索歧义筛查测试结果和BRCA1/2突变体的情绪和筛选行为的影响。