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: 9339152
• 负责人: Sharon A. Savage
• 金额: $ 967.22万
• 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/9339152
• 关键词: Acute Myelocytic Leukemia; Adolescent; Adrenal Gland Cancer; Age; Alleles; American; Aplastic Anemia; Award; BRAF gene; BRCA1 gene; BRCA2 gene; Behavior; Behavioral; Bilateral; Biogenesis; Biological; Bone Marrow Transplantation; Bone Tissue; CBL gene; CEBPA gene; Cervix Neoplasms; Characteristics; Clinical; Clinical Management; Collaborations; Collection; Color; Complex; Consent; Counseling; Cryptorchidism; DICER1 gene; Decision Making; Development; Diamond; Diamond-Blackfan anemia; Disease; Division of Cancer Epidemiology and Genetics; Dubowitz Syndrome; Dyskeratosis Congenita; Dysmyelopoietic Syndromes; Educational workshop; Employee Strikes; Enrollment; Epidemiology; Exposure to; Family; Fanconi' s Anemia; Foundations; Gene-Modified; General Population; Genes; Genetic; Genetic Counseling; Genetic Programming; Genetic Risk; Genetic screening method; Genetic study; Genomics; Genotype; Germ-Line Mutation; Grant; Gynecologic Oncology Group; Hairy Cell Leukemia; Hamartoma; Hereditary Breast Carcinoma; Hereditary Breast and Ovarian Cancer Syndrome; Hereditary Malignant Neoplasm; Hereditary Neoplastic Syndromes; Human Genetics; Human Papillomavirus; Inborn Genetic Diseases; Incidence; Individual; Inherited; International; Jaffe-Campanacci syndrome; Juvenile Myelomonocytic Leukemia; LIG4 gene; Li-Fraumeni Syndrome; Magnetic Resonance Imaging; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of ovary; Malignant neoplasm of testis; Malignant neoplasm of urinary bladder; Manuscripts; Maps; Medical Genetics; MicroRNAs; Modality; Modeling; Molecular; Molecular Biology; Monitor; Moods; Mutation; Myotonic Dystrophy; NF1 gene; Neoplasms; Neurofibromatosis 1; Neutropenia; Nose; Oncogenes; Operative Surgical Procedures; Pancytopenia; Participant; Pathogenesis; Pathogenicity; Pathway Analysis; Pathway interactions; Patients; Peer Review; Penetrance; Perinatal Exposure; Persons; Phenotype; Play; Pleuropulmonary Blastoma; Plexiform Neurofibroma; Predisposition; Psychosocial Assessment and Care; Publications; Publishing; Radial; Radiation; Regimen; Registries; Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Resources; Risk; Risk Reduction; Role; Sampling; Screening for cancer; Seeds; Site; Social Network; Soft tissue sarcoma; Solid Neoplasm; Subgroup; Susceptibility Gene; Syndrome; TINF2 gene; TP53 gene; Test Result; Testing; Thrombocytopenia; Thyroid Gland; Time; Training; Translational Research; United States National Institutes of Health; Variant; Woman; Work; Writing; base; behavioral study; bench to bedside; bone marrow failure syndrome; cancer genetics; cancer prevention; cancer risk; clinical phenotype; cohort; developmental disease; early onset; epidemiologic data; exome sequencing; gene discovery; genetic risk assessment; genetic variant; genome wide association study; genotyping technology; high risk; immune function; improved; in vitro Assay; malignant breast neoplasm; member; men; meningioma; multidisciplinary; mutation carrier; neuropsychiatric disorder; next generation; next generation sequencing; novel; osteosarcoma; patient advocacy group; phosphodiesterase 11a; prospective; psychosocial; screening; telomere; tool; tumor; tumorigenesis; variant of unknown significance

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. The most recent analysis of breast cancer risk in these prospectively-monitored families indicates that mutation-negative women from these mutation-positive families have risks that are similar to those seen in the general population. To date, 20 clinical manuscripts have been published and 40 reports plus 8 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, RTEL1, 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 osteosarcoma, in DBA. Familial Testicular Cancer We have enrolled 733 consented members from 151 newly-ascertained families. Recent findings include confirmation of our association between missense variants in PDE11A and TGCT risk, both familial and sporadic, determining that relatives of men with sporadic bilateral TGCT are at a 12-fold increase in TGCT risk, identification of 16 of the 40 TGCT GWAS risk SNPS, determined that FTGCT is a site-specific cancer syndrome, found an association between in utero exposure to DES and FTGCT, developed a polygenic risk score model that, when combined with cryptorchidism, identifies a subgroup of subjects who are at 50-fold greater TGCT risk. 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 600 members from 180 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. The risks of first and subsequent cancers amongst TP53 mutation carriers in our cohort are very high and nearly 100% of participants have had at least one cancer by age 70 years. The cumulative cancer incidence was 50% by age 31 years in TP53+ women and 46 years in men. Ongoing studies seek to better understand the molecular characteristics of LFS-associated tumors, genetic and environmental modifiers, and the optimal cancer screening regimen. 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 400 members from 80 PPB families, evaluated 130 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 was also published. Publications describing 350 registry-based PPB cases, the first 25 PPB families evaluated, and an analysis of PPB-related thyroid neoplasia are in press as well. 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. This approach is also being applied to studies of familial and sporadic bladder cancer, gene discovery in the inherited bone marrow failure syndromes, and pediatric cancers.

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；培训下一代临床癌症遗传学研究者。头乳房/卵巢癌（HBOC）基于具有广泛临床/流行病学数据和生物学样本的33个BRCA突变阳性家族的前瞻性队列。与这项研究相关的临床活动已经结束，但其生物测量仍在多个转化研究项目中使用。这些前瞻性监测家庭中乳腺癌风险的最新分析表明，这些突变阳性家族的突变阴性妇女的风险与普通人群中的风险相似。迄今为止，已经发表了20份临床手稿，40份报告以及8项正在审查的手稿（与国际联盟CIMBA合作）阐明了与BRCA相关乳腺癌和卵巢癌的渗透率的遗传修饰符。遗传性的骨髓衰竭综合征（IBMFS）研究靶向Fanconi贫血（FA）和相关疾病，其中包括质膜肿瘤，骨髓增生症状综合征（MDS），急性髓样白血病（AML）的高风险。我们已经招募了来自406个IBMFS家庭的1722名成员。主要发现包括对FA-和异常症状的定量估计值（DC）相关的癌症风险，确定这两种疾病中癌症风险的惊人相似性，从而扩大了这些综合症的临床表型，并确定非常短的端粒作为DC的病原体。根据Fanconi贫血研究基金会的赠款，我们正在撰写有关FA患者免疫功能的报告。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。我们已经确定了10个已知的康涅狄格州基因的四个（tinf2，wrap53，rtel1，acd），并提供了第一个证据，表明直流表型包括神经精神疾病的高风险。我们已经分析了北美钻石登记处（DBAR），并在DBA首次记录了癌症，尤其是骨肉瘤的重大风险。家族性睾丸癌我们已招募了来自151个新知名家庭的733名同意成员。 Recent findings include confirmation of our association between missense variants in PDE11A and TGCT risk, both familial and sporadic, determining that relatives of men with sporadic bilateral TGCT are at a 12-fold increase in TGCT risk, identification of 16 of the 40 TGCT GWAS risk SNPS, determined that FTGCT is a site-specific cancer syndrome, found an association between in utero exposure to DES and FTGCT开发了一个多基因风险评分模型，该模型与密码轨道主义相结合时，确定了TGCT风险大50倍的受试者亚组。 Li-fraumeni综合征（LFS）最初由DCEG研究者确定40年前，是一种罕见的，遗传性的疾病，是由种系TP53突变引起的，其早期发作骨和软组织肉瘤，乳腺癌，乳腺癌，肾上腺和脑癌的风险增加。我们已经开始了一项新的LFS研究，该研究已招募了来自180个家庭的600名成员，并提供了遗传咨询和测试，以寻求30％具有TP53突变的LFS患者的新LFS基因，研究了新型的癌症筛查模式（例如，全体MRI）（例如，全体MRI）（例如，试图识别出风险危害风险，危害风险，降低风险危害危险，试图识别遗传改性。我们发表了国际研讨会（2010年11月）的会议记录，该会议厅导致了新的国际LFS研究联盟和第一个LFS患者倡导小组的成立。我们队列中TP53突变携带者中首次癌症的风险非常高，到70岁时，近100％的参与者至少患有一种癌症。 TP53+女性的累积癌症发生率为50％，男性为46岁。正在进行的研究试图更好地了解LFS相关肿瘤，遗传和环境修饰剂以及最佳癌症筛查方案的分子特征。 家族性胸膜肺泡（PPB）是由DICER1种系突变引起的新描述的综合征。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。迄今为止，我们已经招募了来自80个PPB家族的400名成员，在NIH临床中心评估了130名受试者，并对150名受试者进行了DICER1突变测试。利用NIH基准对卧铺奖，我们与研究小组建立了一个合作，该小组发现了DICER1，我们正在与该研究小组进行详细的临床表型和癌症风险量化研究，对这项罕见的新型综合征。 PPB综合征的综述在Genereviews上在线发表，并发表了一份描述与PPB相关的鼻腔软骨瘤Hamartoma的报告。描述了350个基于注册表的PPB病例的出版物，评估了前25个PPB家族以及对PPB相关的甲状腺肿瘤的分析。 神经纤维瘤病1是一种经典的遗传癌易感障碍。我们正在进一步定义其表型并寻求NF1渗透的遗传修饰剂。我们已经表明，Jaffe-campanacci综合征与NF1相反。我们已经确定了特定的遗传变异，这些变异改变了发展NF1相关的CAF-AU-LAIT MACULES，这是一种重要的原始观察证明，并证明野生型NF1等位基因的丧失是丛生的神经纤维瘤的主要驱动因素，是对工业癌症的研究，研究型的研究，是一项研究，研究了pertfor的研究。已经产生了50多个经过同行评审的出版物。 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 BRCA1/2突变载体的筛选行为。 在我们罕见的家族性癌症综合征WES测序项目中，我们在少年JMML，CEBPA，家族AML中的CBL突变和家族性毛状细胞白血病中的CBL突变。我们还表明，杜波维茨综合征是一种综合征复合物，具有多种遗传学，表型重叠的疾病，其中种系Lig4突变起病因的作用。这种方法还应用于家族性和零星膀胱癌，遗传性骨髓衰竭综合征中的基因发现以及儿科癌症的研究。