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 ( 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 ( 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.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Human Genome Research Institute
Zip Code
Jhuraney, Ankita; Velkova, Aneliya; Johnson, Randall C et al. (2015) BRCA1 Circos: a visualisation resource for functional analysis of missense variants. J Med Genet 52:224-30
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
Kolbe, Diana L; DeLoia, Julie A; Porter-Gill, Patricia et al. (2012) Differential analysis of ovarian and endometrial cancers identifies a methylator phenotype. PLoS One 7:e32941
Biswas, Kajal; Das, Ranabir; Alter, Blanche P et al. (2011) A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood 118:2430-42
Wong, Hui-Lee; Peters, Ulrike; Hayes, Richard B et al. (2010) Polymorphisms in the adenomatous polyposis coli (APC) gene and advanced colorectal adenoma risk. Eur J Cancer 46:2457-66
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