A Novel and Rapid System to Classify BRCA2 Missense and Other Variants in Ovarian Cancer
Abstract
A substantial proportion of ovarian cancers are due to alterations, termed mutations, in genetic elements called genes. There are currently 11 distinct demonstrated or suspected ovarian cancer genes that cause this disease in humans when inactivated by mutations. These mutations can either be inherited from a parent or can occur spontaneously. Importantly, mutations in these ovarian cancer genes can potentially occur in any woman, so current guidelines for care recommend genetic screens to identify women with such mutations. This is important because identification of inactivating mutations can be utilized by genetic counselors and healthcare providers to enable preventative measures and/or to select treatment options tailored to that patient’s tumor. Screens for mutations in ovarian cancer genes are based upon sequencing the genetic material (DNA) from patients. Additionally, screens of family members can identify individuals with inherited (germline) mutations that increase their risk of developing ovarian cancer, as well as breast cancer. Importantly, information from such screens can save lives by enabling earlier detection and/or prevention of ovarian cancer. Screens for mutations are also very important for treating ovarian cancer, once diagnosed. Drugs that are utilized to treat ovarian cancer typically damage the genetic material, including genes. Most of the known or suspected ovarian cancer genes have a role in limiting this damage by encoding for proteins that repair it. Platinum compounds, which are a mainstay in the treatment of ovarian cancer, are an example of how mutation can modulate the response to treatment. Platinum compounds are more effective in women with either inherited or spontaneous (somatic) mutations in many of the ovarian cancer genes. As another example of how deleterious mutations can be exploited, poly (ADP-ribose) polymerase (PARP) inhibitors are targeted therapeutics that can selectively kill tumor cells with a genetic defect in these same genes. Thus, identifying patients with either germline or somatic mutations in ovarian cancer genes, which can potentially occur in any woman, helps guide treatment. BRCA2, along with BRCA1, are the two genes that most frequently cause ovarian cancer when mutated. Unfortunately, there is a basic problem with screening for genetic changes in BRCA2 and other genes. This problem is that only some mutations cause cancer, while others are harmless. Thus, we need to distinguish which mutations have the capacity to cause cancer from those which do not. In fact, such predictions currently cannot be made for most mutations of BRCA2. To address this critical issue, we have developed a novel system for testing BRCA2 mutations in order to improve prevention and treatment of ovarian cancer. We can generate and express mutants of BRCA2 in cells that are already genetically defective for BRCA2. Expression of a normal copy of the BRCA2 protein corrects defects in DNA repair in these cells, and we will now determine which mutants of BRCA2 have a compromised ability to repair damage to the genetic material (Aim 1A). Following system validation, we will initiate unbiased tests on 125 unclassified mutations in BRCA2 found in ovarian cancer patients, for which the risk is currently unknown. These assays will be predictive of an increased risk for developing ovarian cancer in women who harbor harmful mutations. This information can then be utilized to guide cancer prevention measures, including surgical measures, as well as counseling concerning environmental and lifestyle hazards that increase cancer risk in these patients. We will also utilize our system to determine whether particular mutations in BRCA2 lead to more effective killing of ovarian cancer cells by PARP inhibitors (Aim 1B). This information can then be utilized to predict which patients are most likely to benefit from treatment with PARP inhibitors, based on mutations they harbor, an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810269
Entities
People
- Paul Andreassen
Organizations
- United States Army