Detecting inherited DNA-repair gene mutations in women with strong family histories of breast cancer


Women with strong personal and family histories of breast cancer are routinely tested for mutations in the BRCA1 and BRCA2 genes, but other gene testing is not generally available or offered. Researchers continue to study the genetic basis of the remaining familial breast cancer cases, and mutations in more than a dozen additional breast cancer risk genes have been identified [26, 28, 37]. Some of these genes are highly penetrant with effect sizes similar to BRCA1 and BRCA2 (>5x increased lifetime risk), while others confer more moderate breast cancer risk (2-5x; Table 2). Testing for most of these gene mutations is not yet available clinically and, more importantly, information in mutation status is difficult to interpret because we lack knowledge of the degree of risk conferred and/or prevalence of mutations in the general population. I seek to validate preliminary risk associations by looking for mutations in these candidate genes in participants from the Arizona Cancer Center High-Risk Breast Cancer Genetics Clinic Bioregistry who do not carry BRCA1 and BRCA2 mutations. I will use massively-parallel high-throughput sequencing technology to assess participant samples for both single nucleotide and copy number variants in 21 genes simultaneously.

Specific Aims

1. To search for both single nucleotide and copy number variants in 20 DNA-repair genes in a cohort of women at high risk of breast cancer, but without an identified BRCA1 or BRCA2 gene mutation using an efficient and cost-effective approach.

2. To develop a database allowing us to follow women with breast-cancer influencing mutations prospectively to determine the breast cancer risk conferred by each mutation in order to improve management for women at high-risk of breast cancer.

 We would like to Thank Phi Beta Psi Sorority for providing funding for our proposal as part of their National Project 2012-2013 Research Grants