Clinical Genetic Studies of Familial and Hereditary Canc

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涉及流行病学，临床，遗传学，行为，统计和实验室方法的跨学科方法中，以确定易感基因在癌症病因学中的作用。该研究项目的主要目标是将分子遗传学的最新进展转化为基于证据的管理策略，用于癌症遗传风险增加的人群。中心研究策略依赖于对癌症易感家庭的个体成员进行详细和细致的评估。 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。一个主要的优先事项仍然是为CGB研究方案（方案02-C-0212）的先前参与者提供BRCA 1/2突变的临床预测性基因检测。这包括将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。迄今为止，另有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个在BRCA 1或BRCA 2中有有害的突变，两个分离CHEK 2变异体，称为1100 delC。我们报道，这种罕见的等位基因使普通人群患乳腺癌的风险增加一倍，并且可能占BRCA 1/2阴性遗传性乳腺癌/卵巢癌家族的一小部分。 31个携带BRCA突变的家庭已经接受了5 - 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前瞻性风险正在量化。这些家庭在BRCA 1/2被克隆之前很久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BRCA 1突变携带者乳腺癌预期风险的影响。我们报道了在接受预防性卵巢切除术的妇女中，乳腺癌的风险降低了62%。另外两篇论文正在准备中：（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的队列进入（在期刊评审中）。 我们的BRCA突变阴性家族构成了评估新的候选高突变率乳腺癌易感基因的资源。我们已经报道了两个这样的基因，（ZBRK 1和BRIP 1），并没有导致乳腺癌和卵巢癌的风险在这些家庭。来自这些家庭的DNA正在汇集在BRCA 1/2突变遗传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，该分析不支持先前的说法，即BRCA 1携带者的男性后代比例低于BRCA 2携带者。我们一直在努力扩大我们收集的DNA样本，从已知的人是阳性或阴性的BRCA 1/2突变，以促进基因表达的遗传修饰剂的研究。除了上述家庭，我们还增加了125个突变阳性家庭，招募到我们的乳腺成像研究，并从GOG 0199，国家卵巢癌预防和早期检测研究的1395名参与者中抽取样本。 我们对1994 - 1995年期间患有前列腺癌的1000名德系以色列人中BRCA 1/2创始者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发病率高出两倍，支持了前列腺癌是BRCA谱系的一部分的假设。相关癌症。

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.