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 (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.
