The role of the BRCA1 and BRCA2 gene in the pathogenesis of breast cancer

分子病理学部分的研究重点是定义基因的变化，这些基因是常见疾病(如癌症和出生缺陷)遗传易感性的基础。目前正在研究的是遗传性乳腺癌和卵巢癌基因BRCA1和BRCA2。这些蛋白质在DNA修复途径中发挥作用。此前，我们发现了哪些蛋白质与BRCA1特异相互作用。我们还发现BRCA1对控制其他基因的表达很重要，并在DNA修复中发挥作用。该项目下的其他实验表明，BRCA1似乎有助于识别和消除可能进展为肿瘤的细胞。我们现在知道，乳腺癌、卵巢癌和前列腺癌风险的增加与这些基因的遗传变异有关，是因为这些突变的蛋白质无法在DNA修复途径中发挥作用。 该实验室不再从事BRCA1和BRCA2基因的实验生物学研究。该实验室在这一领域的主要工作集中于改进和维护一个重要的科学资源，即一个开放访问的乳腺癌基因BRCA1和BRCA2突变数据库。这一科学资源被称为BIC数据库(http://research.nhgri.nih.gov/bic/))，全世界的研究人员都在使用。它仍然是访问量最高的校内研究网站。这些数据的用户样本包括：基础科学家、临床测试实验室、个人患者、商业实体和法律学者。 在过去的一年里，我们扩大了数据库，允许用户评估突变的临床和功能意义。我们正在与Enigma Consortium(enigmaconsortium.org)合作，以获取关于特定突变的医学意义的信息。这些信息现在被捕获并显示在数据库中，从而允许多个额外的实验室提供BRCA1和BRCA2突变测试。 该项目还有助于理解基因组。我们继续与国家生物技术信息中心(NCBI)的研究人员合作，将BIC中的数据显示在中央基因组数据库中。这一点很重要，因为在人类基因组的早期展示中，没有捕获和注释特定于座位的信息。我们将整个BIC变体列表存放到了DBGaP中。作为这一过程的一部分，每个变种都被分配了一个“RS”号。此编号用作该变体的唯一标识。 展望未来，我们正在制定一项过渡计划，以应对我在NHGRI的实验室不再进行主要数据收集和托管的情况。我们正在与NCBI合作，将BIC数据集成到ClinVar数据库(http://www.ncbi.nlm.nih.gov/clinvar/).将BIC数据整合到NCBI的中央基因组数据库具有重要的实际意义。其中最重要的是，BIC数据现在将在三个最重要的基因组浏览器服务器/网站上显示。这为在NHGRI直接访问BIC数据的数千名用户提供了一条在全球范围内分发这些数据的途径。两年前，我们将BIC中包含的所有数据都提供给了ClinVar数据库。值得注意的是，ClinVar还处于发展的早期阶段。来自的用户对ClinVar的反馈发现了可用性问题。在撰写本文时，BIC数据库的访问频率高于ClinVar的BRCA特定页面。我们的计划是让BIC专注于以用户友好的方式显示数据，同时将关键数据库组件过渡到NCBI。从中期来看，在ClinVar达到可以取代BIC数据库的服务和复杂程度之前，将继续维护并行数据库。 该项目不以传统方式出版出版物。这项工作的主要成果是通过直接访问使用的数据库和一套分析工具。这一努力的实际影响是非常显著的。除上述使用统计数据外，BIC数据库还被数百种同行评议的出版物引用。

Research in the Molecular Pathogenesis Section is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Currently under investigation are the inherited breast and ovarian cancer genes, BRCA1 and BRCA2. These proteins function in the DNA repair pathways. Previously, we discovered which proteins specifically interact with BRCA1. We also have found that BRCA1 is important for controlling the expression of other genes and plays a role in DNA repair. Additional experiments under this project have revealed that BRCA1 appears to help in the process of recognizing and eliminating cells that may progress to form tumors. We now know that the increase in breast, ovarian and prostate cancer risk associated with genetic variants in these genes is due to a failure of these mutated proteins to function in the DNA repair pathway. The lab no longer works on the experimental biology of the BRCA1 and BRCA2 genes. The major effort in the lab in this area is focused on improving and maintaining an important scientific resource, an open access database of mutations in the breast cancer genes, BRCA1 and BRCA2. This scientific resource, called the BIC database (http://research.nhgri.nih.gov/bic/) is used by investigators through out the world. It remains the most highly accessed intramural research website. A sample of the users of the data include the following: basic scientists, clinical testing labs, individual patients, commercial entities and legal scholars. In the past year we have expanded the the database to allow users to assess the clinical and functional significance of mutations. We are collaborating with the ENIGMA Consortium (enigmaconsortium.org) to capture information as to the medical significance of specific mutations. This information is now captured and displayed in the database allowing multiple additional labs to offer BRCA1 and BRCA2 mutation testing. This project also has contributed to the understanding of the genome. We continue to work with investigators at the National Center for Biotechnology Information (NCBI) to have the data in the BIC represented in the the central genomic databases. This is important as locus specific information was not captured and annotated in earlier displays of human genome. We deposited the entire list of BIC variants into dbGAP. As part of the process, each variant is assigned an "rs" number. This number serves as a unique identified for the variant. Going forward we are developing a transition plan for when the major data collection and hosting is not longer carried out by my lab in NHGRI. We are working with NCBI to integrate the BIC data into ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/). The integration of the BIC data into the central genome database at NCBI has important practical implications. The most important of which is that the BIC data will now be displayed on the three most important genome browser server/websites. This produces an avenue for global distribution of these data above and beyond the thousands of users who access the BIC data directly at NHGRI. Two years ago year we contributed all of the data contained in the BIC to the ClinVar database. It is noteworthy that ClinVar is in the early stages of evolution. User feedback of from about ClinVar has identified usability issues. At this writing, the BIC database is accessed more frequently than the BRCA specific pages of ClinVar. Our plan going forward to to have BIC focus on displaying the data in a user friendly way while transition the key database components to NCBI. In the medium term, maintaining parallel databases will occur until ClinVar reaches a level of service and sophistication that can replace the BIC database. This project does not produce publications in the traditional fashion. The major fruit of this work is a database and set of analysis tools that are used via direct access. The measured impact of this effort is highly significant. In addition to the usage statistics presented above, the BIC database has been cited by hundreds of peer reviewed publications.