Clinical Genetic Studies of Familial and Hereditary Canc

家族性和遗传性癌症的临床遗传学研究

• 批准号: 7288884
• 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/7288884
• 关键词: Clinical; Genetic; Studies; Familial; Hereditary

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) Hereditary breast and ovarian cancer (HBOC) is a long-standing DCEG research interest. A major priority remains providing clinical predictive genetic testing for BRCA1/2 mutations to prior participants in CGB research protocols (Protocol 02-C-0212). This involves bringing family members to the Clinical Center for genetic risk assessment, counseling, genetic testing and results disclosure. To date, 157 additional family members have undergone genetic risk assessment; nearly all have chosen genetic testing. Currently, we have 60 hereditary breast/ovarian cancer families under active follow-up. Thirty-five have deleterious mutations in BRCA1 or BRCA2, and two are segregating the CHEK2 variant known as 1100delC. We reported that this rare allele doubles the risk of developing breast cancer in the general population, and likely accounts for a small fraction of BRCA1/2-negative hereditary breast/ovarian cancer families. Thirty-one BRCA mutation-carrying families have been under active follow-up from 5 to 35 years; in this cohort, the prospective risks of breast, ovarian, fallopian tube and peritoneal cancers are being quantified. These families were offered risk-reducing surgery long before BRCA1/2 had been cloned. The first analysis quantified the effect of prophylactic oophorectomy on the prospective risk of breast cancer in BRCA1 mutation carriers. We report a 62% decrease in the risk of breast cancer among women who have undergone prophylactic oophorectomy (in press). Two more manuscripts are now in preparation: (1) quantification of the absolute & relative risks of selected cancers; and (2) description of a novel statistical technique for estimating cumulative cancer risk, accounting for competing risks and delayed cohort entry (under journal review). Our BRCA mutation-negative families comprise a resource for evaluating new candidate high-penetrance breast cancer susceptibility genes. We have reported that two such genes, (ZBRK1 and BRIP1), did not contribute to the risk of breast and ovarian cancer in these families. DNA from these families is being pooled in an international study of genetic modifiers of BRCA1/2 penetrance. This cohort of mutation-positive families was also employed in a recent analysis which did not support prior claims that BRCA1 carriers have a lower ratio of male offspring than do BRCA2 carriers. We have been working to expand our collection of DNA samples from persons known to be either positive or negative for BRCA1/2 mutations, to facilitate studies of genetic modifiers of gene expression. In addition to the above families, we have added 125 mutation-positive families recruited to our Breast Imaging Study, and samples from 1395 participants in GOG 0199, the National Ovarian Cancer Prevention and Early Detection Study. 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, supporting the hypothesis that prostate cancer is part of the spectrum of BRCA-related cancers.

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) 遗传性乳腺癌和卵巢癌 (HBOC) 是 DCEG 长期的研究兴趣。主要优先事项仍然是向 CGB 研究方案（方案 02-C-0212）的先前参与者提供 BRCA1/2 突变的临床预测基因检测。这包括带家人到临床中心进行遗传风险评估、咨询、基因检测和结果披露。迄今为止，已有157名家庭成员接受了遗传风险评估；几乎所有人都选择了基因检测。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。其中 35 例在 BRCA1 或 BRCA2 中存在有害突变，其中 2 例分离出称为 1100delC 的 CHEK2 变体。我们报告说，这种罕见的等位基因使一般人群患乳腺癌的风险增加一倍，并且可能只占 BRCA1/2 阴性遗传性乳腺癌/卵巢癌家族的一小部分。 31个BRCA突变携带家族已接受5至35年的积极随访；在这个队列中，乳腺癌、卵巢癌、输卵管癌和腹膜癌的预期风险正在被量化。早在 BRCA1/2 被克隆之前，这些家庭就接受了降低风险的手术。第一项分析量化了预防性卵巢切除术对 BRCA1 突变携带者患乳腺癌的预期风险的影响。我们报告称，接受预防性卵巢切除术的女性患乳腺癌的风险降低了 62%（正在出版）。目前正在准备另外两份手稿：（1）对选定癌症的绝对和相对风险进行量化； (2) 描述一种新的统计技术，用于估计累积癌症风险、考虑竞争风险和延迟队列进入（正在期刊审查中）。 我们的 BRCA 突变阴性家族包含用于评估新的候选高外显率乳腺癌易感基因的资源。我们已经报道，这样的两个基因（ZBRK1 和 BRIP1）不会增加这些家庭患乳腺癌和卵巢癌的风险。来自这些家族的 DNA 正在被汇集到一项关于 BRCA1/2 外显率基因修饰剂的国际研究中。最近的一项分析也采用了这组突变阳性家庭，该分析并不支持之前关于 BRCA1 携带者的男性后代比例低于 BRCA2 携带者的说法。我们一直在努力扩大已知 BRCA1/2 突变阳性或阴性人群的 DNA 样本收集范围，以促进基因表达遗传修饰物的研究。除了上述家庭之外，我们还招募了 125 个突变阳性家庭加入我们的乳腺影像研究，以及来自 GOG 0199（国家卵巢癌预防和早期检测研究）的 1395 名参与者的样本。 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，这支持了前列腺癌是前列腺癌谱系的一部分的假设。 BRCA 相关癌症。