Clinical Genetic Studies of Familial and Hereditary Cancer Syndromes

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。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妇女的风险与一般人群相似。迄今为止，已经发表了20篇临床论文，40篇报告和8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, RTEL1， 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)，并首次记录了DBA患癌症，特别是骨肉瘤的显著风险。家族性睾丸癌我们从151个新确定的家庭中招募了733名同意的成员。最近的研究结果包括确认PDE11A错配变异与TGCT风险（家族性和散发性）之间的关联，确定散发性双侧TGCT男性亲属的TGCT风险增加了12倍，确定40个TGCT GWAS风险snp中的16个，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之间的关联，建立了多基因风险评分模型，当与隐睾相结合时，确定了一个亚组受试者的TGCT风险高出50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，招募了来自180个家庭的600名成员，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（例如全身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。在我们的队列中，TP53突变携带者的首次和后续癌症的风险非常高，几乎100%的参与者在70岁之前至少患有一种癌症。到31岁时，TP53阳性的女性累积癌症发病率为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、遗传和环境修饰因子以及最佳的癌症筛查方案。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。GeneReviews在线发表了一篇关于PPB综合征的综述，并发表了一篇描述PPB相关的鼻软骨间充质错构瘤的报告。出版物描述了350例基于登记的PPB病例，前25个PPB家族的评估，以及PPB相关甲状腺肿瘤的分析也在出版中。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。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。这种方法也被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。

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.