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BRCA1和BRCA2。 这些蛋白质似乎参与DNA修复。此前，我们发现了哪些蛋白质与BRCA1特异性相互作用。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。 我们正在合作一个旨在了解卵巢肿瘤中发生的分子变化的项目。 很大比例的卵巢肿瘤发生在携带BRCA1或BRCA2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。 在过去，我们应用生物信息学方法来探测基因组结构在蛋白质进化中可能发挥的作用。 对BRCA1和BRCA2基因的研究使我们发现了一种特定类型的基因结构与进化变化率之间的新联系。 这一观察结果似乎可以推广到几乎任何基因，并适用于所有后生动物谱系。我们最近完成了对六个基因组中每个基因组的所有外显子的研究。我们在较小样本中观察到的规则在这个较大的集合中得到了证实。 本部分创建并维护了乳腺癌基因BRCA1和BRCA2突变的数据库。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。 在过去的一年中，我们向数据库中添加了信息，使用户能够评估突变的临床和功能意义。作为数据库的扩展，我们正在研究确定BRCA1和BRCA2中哪些突变具有医学意义的方法。我们还增强了我们的图形工具，允许数据库用户浏览BRCA1和BRCA2基因。 在过去的一年里，我们一直在与国家生物技术信息中心（NCBI）的研究人员合作，将BIC中的数据表示在基因组数据库中。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。 这个过程的第一步是将BIC变体的整个列表存款到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。 数据又可以添加到NCBI的ClinVar数据库（http：//www.ncbi.nlm.nih.gov/clinvar/）中。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。

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 appear to be involved in DNA repair. 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 are collaborating 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. In the past, we applied a bioinformatics approach to probe the role that genomic structure may play in protein evolution. The study of the BRCA1 and BRCA2 genes has led us to discover a new connection between a specific type of gene structure and evolutionary rates of changes. This observation appears to be generalizable to almost any gene and holds true across all metazoan lineages. We recently completed the study of all the exons in each of six genomes. The rules we observed for our smaller sample have been confirmed in this larger set. This section created and maintains a 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. In the past year we have added information to the database that will allow users to assess the clinical and functional significance of mutations. As an extension of the database, we are working on methods to determine which mutations in BRCA1 and BRCA2 are of medical significance. We have also enhances our graphical tools that allow users of the database to navigate through the BRCA1 and BRCA2 genes. Over the past year we have been working with investigators at the National Center for Biotechnology Information (NCBI) to have the data in the BIC represented in the genomic database. This is important as locus specific information was not captured and annotated in earlier displays of human genome. The first step in this process was to deposit 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.