Clinical Genetic Studies of Familial / Hereditary Cancer

临床遗传学(CGB)将癌症遗传学中的分子和临床观察整合为一种跨学科的方法，涉及流行病学、临床、遗传学、行为学、统计学和实验室方法，以确定易感基因在癌症病因学中的作用。这项研究计划的主要目标是将分子遗传学的最新显著进展转化为针对癌症遗传风险增加的人的循证管理策略。中央研究战略有赖于对癌症高发家庭的个别成员进行详细和细致的评估。 遗传性乳腺癌/卵巢癌(HBOC) CGB承担的第一个重大临床研究项目代表着DCEG长期致力于遗传性乳腺癌和卵巢癌(HBOC)研究的下一个阶段。对于这些家系，首要任务是将BRCA1/2突变的临床预测性基因检测提供给曾参加过CGB研究方案(议定书02-C-0212)的感兴趣的家庭成员。所有家庭都已被告知他们的突变状态，将感兴趣的家庭成员带到临床中心进行遗传风险评估、咨询、基因检测和结果披露的过程即将完成。在过去的一年里，大约有100名家庭成员接受了基因风险评估，其中大多数人选择了基因检测。目前，我们有60个遗传性乳腺癌/卵巢癌家庭正在积极跟进。35个家庭携带BRCA1或BRCA2的有害突变，另外两个家庭正在分离被称为1100delC的CHEK2变体。其中31个BRCA突变携带者家庭已经进行了超过5年的积极随访(有些长达35年！)，目前正在对这一队列进行分析，以评估在特定易感基因克隆之前更早接受降低风险手术的一组家庭患乳腺癌、卵巢癌、输卵管癌和腹膜癌的潜在风险。我们的BRCA突变阴性家族构成了评估新的候选高渗透性乳腺癌易感基因的资源。我们最近评估了两个这样的基因(ZBRK1和BRIP1)，发现在这些家庭中，这两个基因都不会导致乳腺癌和卵巢癌的风险。来自突变阳性家族的DNA正在被贡献给一个国际合作，该合作正在寻找BRCA1或BRCA2外显性的遗传修饰物。我们对1994-1995年间1000名患有前列腺癌的德裔以色列人进行的BRCA1/2创始人突变患病率的研究证明，突变携带者中前列腺癌的发病率是前者的两倍，这为前列腺癌是BRCA相关癌症的一部分这一假设提供了额外的证据。突变相关的和非突变无关的患者在确诊时的年龄或组织病理学上没有重大差异。这些数据是最近公布的。 我们为这些家庭成员建立了一套新的心理社会和行为研究方案。这些项目正在解决与乳腺癌筛查、早期诊断、与遗传风险评估和检测过程有关的行为、教育和心理社会动力学问题。正在考虑但尚未实施的是关于内源性激素是遗传性乳腺癌风险的贡献者的研究，以及家庭成员关于使用他莫昔芬作为乳腺癌化学预防策略的决策。这项活动利用了我们经验丰富的工作人员的专业知识，其中包括一名遗传顾问、一名精神科社会工作者和一名癌症遗传学研究护士。

The Clinical Genetics Branch (CGB) integrates molecular and clinical observations in cancer genetics into an interdisciplinary approach involving epidemiologic, clinical, genetic, behavioral, statistical and laboratory methods to define the role of susceptibility genes in cancer etiology. The primary goal of this research program is translate recent dramatic advances in molecular genetics into evidence-based management strategies for persons at increased genetic risk of cancer. The central research strategy relies upon the detailed and meticulous assessment of the individual members of cancer-prone families. Hereditary Breast/Ovarian Cancer (HBOC) The first major clinical research project undertaken by CGB represents the next stage in DCEG's long-standing commitment to the study of hereditary breast and ovarian cancer (HBOC). The first priority with regard to these families has been to make clinical predictive genetic testing for BRCA1/2 mutations available to interested family members who had been previous participants in CGB research protocols (Protocol 02-C-0212). All families have been notified of their mutation status, and the process of bringing interested family members to the Clinical Center for genetic risk assessment, counseling, genetic testing and results disclosure is nearing completion. During the past year, ~100 family members have undergone genetic risk assessment, and the majority of those have chosen genetic testing. At the present time, we have 60 hereditary breast/ovarian cancer families under active follow-up. Thirty-five carry deleterious mutations in BRCA1 or BRCA2, and two additional families are segregating the CHEK2 variant known as 1100delC. Thirty-one of the BRCA mutation-carrying families have been under active follow-up for more than 5 years (some as long as 35 years!), and this cohort is currently being analyzed to assess the prospective risks of breast, ovarian, fallopian tube and peritoneal cancers in a set of families that was offered risk-reducing surgery longer before the specific susceptibility genes had been cloned. Our BRCA mutation-negative families comprise a resource for evaluating new candidate highly penetrant breast cancer susceptibility genes. We recently evaluated two such genes (ZBRK1 and BRIP1), and found that neither contributed to the risk of breast and ovarian cancer in these families. DNA from the mutation-positive families is being contributed to an international collaboration which is seeking genetic modifiers of BRCA1 or BRCA2 penetrance. Our study of the prevalence of BRCA1/2 founder mutations in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995 documented a two-fold excess of prostate cancer among mutation carriers, providing additional evidence in support of the hypothesis that prostate cancer is part of the spectrum of BRCA-related cancers. No major differences in age at diagnosis or in histopathology between mutation-related and mutation-unrelated have been identified. These data were recently published. We have mounted a new set of psychosocial and behavioral research protocols for these same family members. These projects are addressing issues related to breast cancer screening, early diagnosis, behavioral, educational and psychosocial dynamics related to the process of genetic risk assessment and testing. Under consideration, but not yet implemented, are studies of endogenous hormones as contributors to the risk of hereditary breast cancer, and decision-making by family members related to the use of tamoxifen as a breast cancer chemoprevention strategy. This activity draws upon the expertise of our highly experienced staff, which includes a genetic counselor, a psychiatric social worker and a cancer genetics research nurse.