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结果整合到涉及流行病学，临床，遗传，行为，统计，统计和实验室方法的跨学科方法中，以定义易感性基因在癌症病因中的作用。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基于循证的管理策略，以增加癌症遗传风险。中央研究策略依赖于对容易癌症家庭的个体成员进行的详细和细致的评估。 遗传性乳腺/卵巢癌（HBOC） CGB进行的第一个主要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）的下一个阶段。关于这些家族的首要任务是对曾经是CGB研究方案参与者的感兴趣的家庭成员提供的BRCA1/2突变的临床预测基因测试（协议02-C-0212）。所有家庭都已通知其突变状态，并将有兴趣的家庭成员带到临床风险评估，咨询，基因检测和结果披露的过程接近完成。在过去的一年中，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/卵巢癌家庭在积极的随访下。 BRCA1或BRCA2中的35个携带有害突变，另外两个家庭正在将CHEK2变体隔离为1100delc。 BRCA突变家庭的三十一个已经进行了5年的积极随访（长达35年！），目前正在分析此同类群体，以评估乳房，卵巢，输卵管管和腹膜癌的前瞻性风险，这些家庭在提供了更长时间的风险较长的家族中，这些家族更长地提供了较长的风险手术。我们的BRCA突变阴性家族包括一种评估新候选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），发现这两种基因都没有导致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正在为国际合作提供了贡献，该合作正在寻求BRCA1或BRCA2渗透的遗传修饰符。我们对1994年至1995年在1000个具有前列腺癌的Ashkenazi Israelis系列中BRCA1/2创始人突变患病率的研究记录了突变携带者中的前列腺癌超过两倍，提供了其他证据，以支持前列腺癌是BRCA癌症的一部分。尚未确定与突变相关和突变无关的诊断年龄或组织病理学年龄的主要差异。这些数据最近发表了。 我们为这些同一家庭成员安装了一套新的社会心理和行为研究方案。这些项目正在解决与乳腺癌筛查，早期诊断，行为，教育和社会心理动态有关的问题，与遗传风险评估和测试过程有关。正在考虑的是，但尚未实施，是对内源激素的研究，是造成遗传性乳腺癌风险的原因，以及与使用他莫昔芬作为乳腺癌化学预防策略有关的家庭成员的决策。这项活动借鉴了我们经验丰富的员工的专业知识，其中包括遗传辅导员，精神科社会工作者和癌症遗传学研究护士。