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 ( 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 ( 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 ( 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 ( 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.

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National Human Genome Research Institute
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McGaughey, David M; Abaan, Hatice Ozel; Miller, Ryan M et al. (2014) Genomics of CpG methylation in developing and developed zebrafish. G3 (Bethesda) 4:861-9
Palavalli, Lavanya H; Prickett, Todd D; Wunderlich, John R et al. (2009) Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet 41:518-20
Greenblatt, Marc S; Brody, Lawrence C; Foulkes, William D et al. (2008) Locus-specific databases and recommendations to strengthen their contribution to the classification of variants in cancer susceptibility genes. Hum Mutat 29:1273-81