The identification of the two major breast cancer predisposition genes, BRCA1 and BRCA2, has heralded an era of genetic risk assessment which in turn has helped to facilitate the development of new strategies for early detection and prevention of breast cancer in the high-risk individual. However remaining unanswered questions regarding genetic risk assessment involve the wide range of penetrance observed in mutation carriers with respect to incidence of cancer development, age of onset and cancer type. In addition, it has been hypothesized but not proven that additional inherited genetic traits as well as environmental factors modulate the effect of a BRCA1 or BRCA2 mutation. The BRFFCA1 gene is now known to play a role in DNA repair. It is hypothesized that persons who carry a mutation of BRCA1 may be at risk of accumulating other signs of genetic damage more rapidly and more extensively than individuals with normal copies of the BRCA1 genes. This end result of this accumulation of genetic damage is the development of breast cancer at an early stage. In order to ultimately reduce breast cancer mortality due to inherited mutation of the BRCA1 gene, a better understanding is needed of the intermediate pathways of due to inherited mutation of the BRCA1 gene, a better understanding is needed of the intermediate pathways of genetic change leading to breast cancer in the predisposed individual along with a better understanding of the susceptibility of the heterozygous individual to DNA damaging agents. In this proposal we will characterize on a chromosomal level the phenotypic manifestation of BRCA1 mutations. The theme of this proposal will involve the elucidation of various manifestations of genomic instability in cells that are heterozygously mutant for BRCA1, with the goal of developing diagnostic tests to further assess risk which will then assist in making therapeutic interventions. The extent of chromosomal carriers will be determined in this study. We will determine if chromosomal instability observed in peripheral blood lymphocytes is reflective of chromosomal instability in breast epithelial cells. The degree of chromosomal instability will be correlated with the development of cancer in BRCA1 mutation carriers. We will determine if occasional loss of alleles in susceptible tissue is a marker of risk. This study targets key points in the pathway of tumor development and progression in BRCA1 mutation carriers. This will provide a phenotypic marker, which may be useful in refining cancer risk assessment in the BRCA1 mutation carrier. This will have the translational potential for developing new diagnostic tests, which may then influence the development of intervention strategies to reduce risk.
