"The role of genetic modifiers in DNA repair and breast cancer"
Though it has been well-established that germline mutations in a number of DNA repair genes (e.g. BRCA1, BRCA2, ATM, P53) lead to highly penetrant familial breast cancer, these instances are rare. It is hypothesized that many common forms of breast cancer are also linked to DNA repair defects, but in this case due to epistatic genetic interactions of two or more alleles. Based on this, we propose that DNA damage sensitivity may serve as an intermediate phenotype for cancer susceptibility. As such, our laboratory has developed a rapid screening approach for identifying novel low penetrance breast cancer susceptibility alleles which leverages the model system S. cerevisiae for genome-wide screening and uses sensitivity to DNA damaging agents as an intermediate phenotype for cancer susceptibility. In this study, we will screen for genes that show synthetic DNA damage sensitivity with tel1ƒ´, the yeast homolog of the human tumor suppressor and DNA damage sensor, ATM. Using methods that integrate both computational biology and molecular genetics, we will characterize the identified synthetic interactions for those that are conserved in human mammary epithelial cells and test for those that contribute to cancer susceptibility. Identification of low penetrance breast cancer alleles would have a significant public health benefit in both cancer screening and evolving treatment strategies, and we hope to further elucidate the link between tumorigenesis and DNA repair defects.