Clinical Genetic Studies of Familial / Hereditary Cancer

家族性/遗传性癌症的临床遗传学研究

• 批准号: 6944663
• 负责人: MARK H GREENE
• 金额: --
• 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/6944663
• 关键词: bone marrow disorder; brca gene; breast neoplasms; cancer prevention; cancer risk; early diagnosis; family genetics; female reproductive system neoplasm; genetic counseling; genetic disorder; genetic markers; genetic screening; genetic susceptibility; human genetic material tag; human papillomavirus; human subject; longitudinal human study; neoplasm /cancer diagnosis; neoplasm /cancer education; neoplasm /cancer epidemiology; neoplasm /cancer genetics; ovary neoplasms; patient oriented research; pediatrics; psychological aspect of cancer; questionnaires; testis neoplasms

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.

临床遗传学分支 (CGB) 将癌症遗传学中的分子和临床观察整合到跨学科方法中，涉及流行病学、临床、遗传学、行为、统计和实验室方法，以确定易感基因在癌症病因学中的作用。该研究计划的主要目标是将分子遗传学的最新进展转化为针对癌症遗传风险增加人群的循证管理策略。中心研究策略依赖于对癌症易发家庭的个体成员进行详细而细致的评估。 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了 DCEG 长期致力于遗传性乳腺癌和卵巢癌 (HBOC) 研究的下一阶段。对于这些家庭来说，首要任务是向曾参与 CGB 研究方案（方案 02-C-0212）的感兴趣的家庭成员提供 BRCA1/2 突变的临床预测基因检测。所有家庭都已被告知其突变状态，并且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已接近完成。去年，约有100名家庭成员接受了遗传风险评估，其中大多数选择了基因检测。目前，我们有60个遗传性乳腺癌/卵巢癌家族正在积极随访中。 35 个家族携带 BRCA1 或 BRCA2 有害突变，另外两个家族正在分离被称为 1100delC 的 CHEK2 变体。其中 31 个 BRCA 突变携带家族已接受超过 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，以评估乳腺癌、卵巢癌、输卵管癌的前瞻性风险。在特定易感基因被克隆之前，一组家庭中的管癌和腹膜癌患者接受了降低风险的手术。我们的 BRCA 突变阴性家族包含用于评估新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），发现这两个基因都不会增加这些家庭患乳腺癌和卵巢癌的风险。来自突变阳性家族的 DNA 正在被贡献给一项国际合作，该合作正在寻求 BRCA1 或 BRCA2 外显率的基因修饰剂。我们对 1994 年至 1995 年间 1000 名患有前列腺癌的德系以色列人中 BRCA1/2 创始人突变的患病率进行了研究，记录了突变携带者中前列腺癌的患病率是原来的两倍，这为支持前列腺癌是前列腺癌这一假设提供了额外的证据。 BRCA 相关癌症谱系的一部分。突变相关和突变无关之间在诊断时年龄或组织病理学方面没有发现重大差异。这些数据最近公布。 我们为这些家庭成员制定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、与遗传风险评估和测试过程相关的行为、教育和社会心理动态相关的问题。正在考虑但尚未实施的是内源性激素作为遗传性乳腺癌风险因素的研究，以及家庭成员与使用他莫昔芬作为乳腺癌化学预防策略相关的决策。这项活动利用了我们经验丰富的员工的专业知识，其中包括一名遗传咨询师、一名精神科社会工作者和一名癌症遗传学研究护士。