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

基本信息

批准号：
9770258
负责人：
Alexander Pemov
金额：
$ 796.96万
依托单位：
DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
依托单位国家：
美国
项目类别：
财政年份：
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/9770258
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 Breast Cancer Risk Factor 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 Enrollment Epidemiology Etiology Exposure to Family Fanconi&apos s Anemia Foundations General Population Genes Genetic Genetic Counseling 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 Disease Hereditary Malignant Neoplasm Hereditary Neoplastic Syndromes Human Genetics Human Papillomavirus 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 Operative Surgical Procedures Pancytopenia Participant Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Patients Peer Review Penetrance Persons Phenotype Play Pleuropulmonary Blastoma Plexiform Neurofibroma Predisposition Prospective cohort 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 prenatal exposure programs prospective psychosocial screening telomere tool tumor tumorigenesis variant of unknown significance

项目摘要

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.

临床遗传学分部 (CGB) 是 NCI 开展校内临床癌症遗传学转化研究活动的基地。 CGB 带来了多学科、流行病学的视角：了解基因在癌症病因、治疗和预防中的作用；为高风险个人和家庭制定综合管理策略；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) 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本。与这项研究相关的临床活动已经结束，但其生物样本继续用于多个转化研究项目。对这些前瞻性监测家庭中乳腺癌风险的最新分析表明，来自这些突变阳性家庭的突变阴性女性的风险与普通人群中的风险相似。迄今为止，已发表 20 份临床手稿，40 份报告和 8 份正在审查的手稿（与国际财团 CIMBA 合作），阐明了 BRCA 相关乳腺癌和卵巢癌外显率的基因修饰因素。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，包括高风险再生障碍性贫血、骨髓增生异常综合征 (MDS)、急性髓系白血病 (AML) 和特定实体瘤。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 和先天性角化不良 (DC) 相关癌症风险的定量估计，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，以及确定非常短的端粒作为 DC 的特征。在范可尼贫血研究基金会的资助下，我们正在撰写一份关于 FA 患者免疫功能的报告。我们合作开发了一种体外检测方法，用于检测 FANCD1/BRCA2 中意义不明的错义变异的致病性。我们已经确定了 10 个已知先天性角化不良基因中的 4 个（TINF2、WRAP53、RTEL1、ACD），并提供了第一个证据表明 DC 表型包含神经精神疾病的高风险。我们分析了北美 Diamond-Blackfan 登记处 (DBAR)，并首次记录了 DBA 中癌症（特别是骨肉瘤）的重大风险。家族性睾丸癌我们已招募了来自 151 个新确定家庭的 733 名同意成员。最近的研究结果包括确认 PDE11A 错义变异与 TGCT 风险（家族性和散发性）之间的关联，确定患有散发性双侧 TGCT 的男性亲属的 TGCT 风险增加 12 倍，识别 40 名 TGCT GWAS 风险中的 16 名SNPS 确定 FTGCT 是一种位点特异性癌症综合征，发现子宫内暴露于 DES 和 FTGCT 之间存在关联，开发了多基因风险评分模型与隐睾症相结合，可以识别出 TGCT 风险高出 50 倍的受试者亚组。 Li-Fraumeni 综合征 (LFS) 最初由 DCEG 研究人员在 40 年前发现，是一种由种系 TP53 突变引起的罕见遗传性疾病，会增加早发性骨癌和软组织肉瘤、乳腺癌、肾上腺癌和脑癌的风险。我们启动了一项新的 LFS 研究，招募了来自 180 个家庭的 600 名成员，并提供遗传咨询和测试，在 30% 具有 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（例如，身体 MRI），试图识别风险的遗传修饰因素，并研究降低癌症风险的策略。我们出版了一次国际研讨会（2010 年 11 月）的会议记录，该研讨会促成了新的国际 LFS 研究联盟和第一个 LFS 患者倡导小组的成立。我们的队列中 TP53 突变携带者首次和后续癌症的风险非常高，近 100% 的参与者在 70 岁时至少患有一种癌症。 TP53+ 女性 31 岁时的累积癌症发病率为 50%，男性为 46 岁。正在进行的研究旨在更好地了解 LFS 相关肿瘤的分子特征、遗传和环境调节剂以及最佳癌症筛查方案。家族性胸膜肺母细胞瘤 (PPB) 是一种新近描述的综合征，由 DICER1 种系突变引起；它代表了第一个已知的由 microRNA 生物发生改变引起的癌症易感综合症。迄今为止，我们已经招募了来自 80 个 PPB 家庭的 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 突变检测。利用 NIH Bench-to-Bedside 奖项，我们与发现 DICER1 的研究小组建立了合作，我们正在与该研究小组一起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。 GeneReviews 在线发表了一篇关于 PPB 综合征的综述，还发表了一篇描述 PPB 相关鼻软骨间质错构瘤的报告。描述 350 个基于登记的 PPB 病例、评估的前 25 个 PPB 家族以及 PPB 相关甲状腺肿瘤分析的出版物也已出版。神经纤维瘤病 1 是一种典型的遗传性癌症易感性疾病。我们正在进一步定义其表型并寻找 NF1 外显率的遗传修饰剂。我们已经证明 Jaffe-Campanacci 综合征与 NF1 具有等位基因。我们已经确定了特定的遗传变异，这些变异可以改变发生 NF1 相关咖啡斑的风险，这是一项重要的原理验证观察，并证明野生型 NF1 等位基因的丢失是丛状神经纤维瘤肿瘤发生的主要驱动因素.家族性癌症的遗传咨询、心理社会和行为研究是 CGB 研究组合中每项研究的重要组成部分，该研究已产生 50 多项经过同行评审的研究出版物。我们扩展了新的遗传咨询工具的应用，例如彩色生态遗传学关系图，从 HBOC 到 FTGCT，应用了新的分析策略，例如社交网络分析，分析了 GOG-199 中与选择手术或筛查相关的变量，评估了 FA 家族内骨髓移植决策的决定因素，并探讨了模糊和假阳性筛查结果对 BRCA1/2 突变携带者情绪和筛查行为的影响。在我们的罕见家族癌症综合征 WES 测序项目中，我们在病因学上发现了青少年 JMML 中的 CBL 突变、家族性 AML 中的 CEBPA 以及家族性毛细胞白血病中的 BRAF 突变。我们还表明，Dubowitz 综合征是一种由多种遗传上不同、表型重叠的疾病组成的综合征，其中种系 LIG4 突变发挥着病因作用。这种方法还应用于家族性和散发性膀胱癌、遗传性骨髓衰竭综合征的基因发现和儿科癌症的研究。