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

遗传和环境相互作用科的研究重点是确定遗传易感性基础上的基因变化，如癌症和出生缺陷。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修复途径中起作用。之前，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进展形成肿瘤的细胞。现在已经确定，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，这是由于这些突变蛋白在DNA修复途径中不起作用。

Research in the Genetics and Environment Interaction 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. It is now well established 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. Our major effort over the last five years in this area was focused on improving and maintaining a scientific resource, known as the BIC database. This important scientific resource is an open access database of mutations in the breast cancer genes, BRCA1 and BRCA2. This database (http://research.nhgri.nih.gov/bic/) is used by investigators throughout the world. For the past two decades, it has been the most highly accessed research resource on NHGRIs 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. The database allows users to assess the clinical and functional significance of mutations. This information is now captured and displayed in the database allowing multiple additional labs to offer BRCA1 and BRCA2 mutation testing. This project contributed to the understanding of the genome. We worked with investigators at the National Center for Biotechnology Information (NCBI) to have the data in the BIC represented in 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 identifier for the variant. Over the last two years, we have transitioned away from being a data collection center for BRCA data. During the next reporting period we plan to transfer all data collection and curation efforts to other researchers (see below). Outside users wishing to deposit data on the BRCA1 and BRCA2 genes will be directed to CLINVAR. As part of this transition plan, we now refer investigators to ClinVar. The group at NCBI has greatly expanded the CLINVAR database. All of the data collected in the BIC database has been duplicated and transferred to NCBI to and integrated into the ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/). The integration of the BIC data into the central genome database at NCBI has had several important practical implications. The most important is that the BIC data is now 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. Five years ago, we contributed all of the data contained in the BIC to the prototype of the ClinVar database. User feedback from those looking at BRCA data in ClinVar has identified usability issues with ClinVar. This suggests that there remains a role for the BIC database for the near future. We do not anticipate that our effort will be needed over the long term. Our plan is to work with the databases that will replace the BIC to display BRCA variation data in a user friendly way. In the medium term, maintaining parallel databases will occur until ClinVar reaches a level of service and sophistication that can replace the BIC database. We have also shared the entirety of the BIC database with the BRCA Challenge project. This project was originally sponsored by the Global Alliance for Genomics and Health. This international organization is focused on aiding the dissemination genomics information worldwide. The BRCA Challenge has matured rapidly and been renamed the BRCA Exchange (https://brcaexchange.org). BRCA Exchange staff have gathered additional BRCA mutation data from several sources and have a stated goal to gather data from parts of the world that do not currently share their data. The main output of this project is the data itself and the database resources that it provides to the research community. As such, this project does not routinely produce scientific publications. Using outdated metrics for productivity and return on investment will not capture the value of this project. The major fruit of this work was a database and set of analysis tools that are used via direct access. The impact of the database is measured in terms of membership applications, download statistics and page views. The measured impact of this effort is highly significant. In addition to the usage statistics presented above, the BIC database has been cited by thousands of peer reviewed publications. In terms of other investment of NHGRI into scientific databases, the BIC database remains the most accessed scientific data resource at NHGRI. This rank has held constant for more than two decades. The impact of this investment has only been amplified by the active distribution of these data to others. CLINVAR and the BRCAExchange databases are well on their way to being the new standards for BRCA data resources. This means that the BIC database and this project are close to completion. Over the next year we will work to convert the BIC database to a data archive. This will preserve the data that has been used as the basis for many publications while acknowledging that this resource will no longer be standard reference in this area. While this archive will no longer contain the most up to date information on the BRCA genes, it will continue to serve as a research resource for scholars studying the history and evolution of data sharing.