Breast cancer is the second leading cause of death in American women and family history is known to be a significant factor for the development of this disease. BRCA1, the breast cancer susceptibility gene located on chromosome 17 has recently been isolated. Almost simultaneously, chromosome 13q12-13 was identified as the locale of another such gene by genetic linkage analysis. In collaboration with the group responsible for isolation of BRCA1, we plan to further localize and ultimately isolate BRCA2. Our goals include identification additional families with evidence of linkage between breast cancer and genetic markers flanking BRCA2. These families will be studied for informative meiotic recombination events that will narrow the BRCA2 candidate interval and will be used for mutation analysis in testing BRCA2 candidate genes. Peripheral blood lymphocytes will be collected from living family members and paraffin-embedded tissue will be utilized as a source of DNA for linkage analysis from deceased family members. One affected family member will also undergo karyotyping in an attempt to identify balanced translocations or other visible chromosomal abnormalities which may involve the BRCA2 locus. Tumors from affected individuals in linked families will be studied for LOH in the BRCA2 candidate region as a means of further narrowing the candidate region. A physical map of the BRCA2 region is being constructed by our collaborators. The map already includes full coverage by yeast artificial chromosomes (YACs) and is approximately 50% covered with bacterial artificial chromosomes (BACs) and P1 clones. BAC and P1 genomic clones encompassed by the most tightly linked markers will be searched for potential transcripts by exon trapping and direct selection. Potential candidate cDNAs will be analyzed for the presence of germline mutations in affected individuals from BRCA2-linked families. The presence of germline mutations in families with evidence of linkage to BRCA2 will serve to identify a candidate gene as BRCA2. Once BRCA2 has been isolated (by us or others), we will expand our search for BRCA2 mutations to a bank of DNA collected from more than 300 women with a family history of breast cancer and/or a diagnosis of breast cancer before the age of 40. This panel of samples should be very useful in describing the spectrum of BRCA2 mutations in such a population, and these data will be added to an international study of genotype/phenotype correlation in families with inherited susceptibility to breast cancer as a result of germline mutations in BRCA1 or BRCA2. Perhaps of greatest significance however is that identification of BRCA2 will be pivotal in our understanding of the development of breast cancer, and will hasten the time when we can accurately define a cohort of women at very high risk of developing breast cancer and prevent the development of this devasting and potentially fatal disease.
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