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

分子发病机制部分的研究重点是定义基因的变化，这些基因是遗传易感性对常见疾病如癌症和出生缺陷的基础。目前正在研究的是遗传性乳腺癌和卵巢癌基因BRCA 1和BRCA 2。 这些蛋白质在DNA修复途径中起作用。 之前，我们发现了哪些蛋白质与BRCA 1特异性相互作用。我们还发现BRCA 1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，BRCA 1似乎有助于识别和消除可能形成肿瘤的细胞。我们现在知道，与这些基因中的遗传变异相关的乳腺癌、卵巢癌和前列腺癌风险的增加是由于这些突变的蛋白质在DNA修复途径中无法发挥作用。 我们继续在一个旨在了解卵巢肿瘤中发生的分子变化的项目上合作。 很大比例的卵巢肿瘤发生在携带BRCA 1或BRCA 2基因突变的女性中。 我们最近发现了一些基因的变化，这些变化可能会将卵巢肿瘤分为不同的病理亚型。这些变化现在可以与特定的临床结果和对治疗的反应相关。 该实验室在这一领域的主要工作集中在改善和维护一个重要的科学资源，即乳腺癌基因BRCA 1和BRCA 2突变的开放获取数据库。 这一科学资源被称为BIC数据库（http：//research.nhgri.nih.gov/bic/），供全世界的研究人员使用。它仍然是访问量最大的校内研究网站。 在过去的一年中，我们扩展了数据库，允许用户评估突变的临床和功能意义。 我们正在与ENIGMA联盟（enigmaconsortium.org）合作，以获取有关特定突变的医学意义的信息。 这些信息的捕获和显示将允许多个额外的实验室提供BRCA 1和BRCA 2突变检测。在过去的一年里，我们开始从一个主要的诊断实验室接收突变数据，以显示结果。这将为该领域的所有人提供一个大型突变数据集（8，000个条目）。 我们还与共享临床报告项目（http：//www.example.com）合作，直接从诊所、临床医生和患者那里收集BRCA 1和BRCA 2变体。sharingclinicalreports.org 这项重要的努力是捕捉信息，否则将失去科学。我们预计，该项目将在2014年产生数千个额外的数据条目。 该项目也有助于对基因组的理解。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中的数据在中央基因组数据库中表示。这是重要的，因为基因座特异性信息在人类基因组的早期展示中没有被捕获和注释。 我们将BIC变体的整个列表存放到dbGAP中。 作为该过程的一部分，每个变体都被分配了一个“rs”编号。 该编号用作变体的唯一标识符。 这些数据反过来可以添加到NCBI的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中具有重要的实际意义。 其中最重要的是，BIC数据现在将显示在三个最重要的基因组浏览器服务器/网站上。 这为这些数据的全球分布提供了一条途径，而不仅仅是在NHGRI直接访问BIC数据的数千名用户。 该项目不以传统方式制作出版物。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非常显著。 除了上面介绍的使用统计数据外，BIC数据库还被数百篇同行评审的出版物引用。

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. We continue collaborate on a project designed to understand the molecular changes that occur in ovarian tumors. A large percentage of ovarian tumors occur in women who carry mutations in their BRCA1 or BRCA2 genes. We have recently identified changes in genes that may classify ovarian tumors into different pathological subtypes. These changes can now be related to specific clinical outcomes and responses to treatment. 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 accessed intramural research website. In the past year we 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. The capture and display of this information will allow multiple additional labs to offer BRCA1 and BRCA2 mutation testing. In the past year we began to receive mutation data from a major diagnostic lab to display the results. This will provide all those in the field with a large mutation dataset (8,000 entries). We have also worked with the Sharing Clinical Reports project (http://sharingclinicalreports.org) to collect BRCA1 and BRCA2 variants directly from clinics, clinicians and patient. This important effort is capturing information that would otherwise be lost to science. We expect that this project will produce thousands of additional data entries in 2014. 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. The data in turn can be added to the ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/) at NCBI. 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. 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 is cite in hundreds of peer reviewed publications.