The BRCA1 gene, located at chromosome 17q21, has been shown to be mutated in hundreds of families with inherited suscepticibility to breast and ovarian cancer. About 5-10 percent of cases of breast and ovarian cancer are believed to be due to such heritable defects with over half of these involving BRCA1. Frequent observation of loss of heterozygosity apparently affecting the BRCA1 locus in sporadic tumors led to early expectations that the BRCA1 gene plays a significant role in the etiology of the much larger group of sporadic breast and ovarian cancers. The cloning of the gene has not resulted in the accumulation of significant evidence implying any such role. A widely accepted implication is that the carcinogenic pathway in cells with a BRCA1 mutation is distinct from that followed by cells without such a mutation and that frequent loss of heterozygosity observed at the 17q21 locus in sporadic tumors is due to one or more distinct tumor suppressor genes at this site. The experiments proposed here are designed to address the possibility that genetic inactivation of BRCA1 is, in fact, an important precursor to tumorigenesis in some proportion of sporadic cases, and that it occurs by genetic mechanisms involving chromosomal rearrangement that have not previously been adequately considered or tested for. They plan to use DNA probes spanning both the unique parts of the BRCA1 gene as well as the newly-recognized promoter duplication segment to detect and characterize specific gene structural alterations in a large set of breast tumor samples. The experimental materials and methods will also be useful or the identification of any tumor suppressor gene that lies in the neighborhood of BRCA1 in the event that study results are consistent with the inference that such a gene exists.
| Barker, D F (2000) Direct genomic multiplex PCR for BRCA1 and application to mutation detection by single-strand conformation and heteroduplex analysis. Hum Mutat 16:334-44 |
| Liu, X; Barker, D F (1999) Evidence for effective suppression of recombination in the chromosome 17q21 segment spanning RNU2-BRCA1. Am J Hum Genet 64:1427-39 |
