Abstract A018: Genomic evaluation of inherited predisposition to breast cancer in women from the University of Arizona Cancer Center High Risk Breast Cancer Genetics Clinic

Background: One in 8 women will develop breast cancer over the course of her lifetime, making it the most common cancer affecting women and the 2nd leading cause of cancer death. 20% of women with breast cancer have 1 or more family members who have also been diagnosed. In 25% of familial cases, cancer occurs in both the breast and ovaries and is attributable to deleterious mutations in BRCA1/BRCA2 DNA repair genes. A woman with a BRCA gene mutation has an 85% lifetime risk for developing breast cancer and 20-60% risk for ovarian cancer. The remaining 75% of susceptibility is polygenic in nature and a large number of low-penetrance genes are involved. This project builds on the discovery of new breast cancer influencing genes that interact with BRCA1 and BRCA2 to function in DNA repair. Here, we utilize next generation parallel sequencing techniques to determine if 89 genes of interest thought to play a role in breast cancer susceptibility are found in women with strong family histories of breast cancer enrolled in the University of Arizona Cancer Center High Risk Breast Cancer Genetics Clinic (UACC BCGC). Methods: The UACC BCGC is a unique and well-developed resource that is vital to the success of this translational project. The purpose of the high risk breast cancer genetics clinic is to provide cancer risk assessment and to manage surveillance and risk-reduction strategies in a cohort of high-risk women. This University of Arizona IRB-approved registry for epidemiologic and medical record information has been accruing for the past five years, and 182 subjects are currently enrolled with additional women being regularly recruited. Fifty-one (28%) of current UACC BCGC registry participants have identified BRCA1 or BRCA2 mutations and this study seeks genetic risk factors for cancer in other registry participants. The 72% of participants in the UACC BCGC database without identified BRCA mutations fall into four categories: 1) untested for BRCA mutations, 2) affected relative tests negative for deleterious BRCA mutation, 3) unaffected participant tests negative for deleterious BRCA mutation, and 4) BRCA negative participant diagnosed with breast cancer or “pre cancer”. Participants in categories 1, 2, and 4 were recruited. Genomic DNA was captured from the initial cohort of BCGC samples using Agilent Technologies HaloPlex protocols to enable additional analysis of novel custom genes of interest in addition to the University of Washington developed BROCA panel. Captured library DNA was denatured and subjected to cluster amplification on a Paired End Flow Cell in paired-end libraries with ~200 bp insert size, and sequenced on an Illumina HiSeq2000 instrument with 100 bp read lengths. Results: We expect that our preliminary analysis will show variation within these 89 genes may explain up to 50% of breast cancer risk in families with a strong pattern of breast cancer enrolled in the UACC BCGC. It is our hope that discovering the genetic risk factors at work in high risk families will help clarify individual risk and that this genetic information can be utilized to improve the management of at-risk women. Population frequency of variation is a major thrust of this project and future studies will probe penetrance. Long terms goals include expanding our recruitment of patients and their family members to allow prospective analysis to determine if these heritable mutations correlate with development of other types of cancer. Discussion: 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. 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). Testing for most of these gene mutations is not yet available clinically and information in mutation status is difficult to interpret because we lack knowledge of the degree of risk conferred and/or the prevalence of these mutations in the general population. Discovering genetic risk factors at work in high risk families using our expanded panel at the UACC BCGC will help clarify individual risk and this genetic information can be utilized to improve the management of at-risk women. Identifying these patients is important because we can suggest specific cancer prevention options based on genetics. We can increase the chance of identifying cancer early and at a more treatable non-invasive stage by using intensive screening, recommending preventive medication, and/or risk reducing surgery to decrease the chance of developing invasive breast cancer in high risk individuals. Citation Format: Ateefa Chaudhury, Corina Mauss, Joanne Jeter, Christina Laukaitis. Genomic evaluation of inherited predisposition to breast cancer in women from the University of Arizona Cancer Center High Risk Breast Cancer Genetics Clinic. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A018.