Understanding Inherited Ovarian Cancer Beyond BRCA1 and BRCA2
Abstract
Ovarian cancer is the deadliest gynecologic malignancy. Nearly 20% of women with ovarian cancer have inherited mutations that likely caused their cancer, indicating that a substantial proportion of cases could have been prevented if the woman had known she was at risk. Women with mutations in the BRCA1 and BRCA2 genes are known to be at high risk of developing ovarian cancer, and it is recommended that these women have their ovaries and fallopian tubes removed after they have completed childbearing. This surgical intervention is highly effective if done with appropriate timing, preventing nearly all ovarian cancers and reducing the risk of dying. However, these benefits must be balanced against the risks of undergoing surgery, premature menopause, and loss of childbearing potential. Of women with ovarian cancer who are found to have inherited mutations, around 20-25% of these mutation-carriers have mutations in genes other than BRCA1 and BRCA2, in genes such as BRIP1, RAD51C, RAD51D, PALB2, and others. These “non-BRCA” genes have much more limited information in regard to the risk of ovarian cancer, making it very challenging to give medical advice about cancer prevention. They may also be candidates for surgical removal of the fallopian tubes and ovaries, and these women need better information to help them weigh the risks and benefits. The objective of this proposal is to improve the understanding of inherited ovarian cancer by determining more precise estimates of ovarian cancer risk with mutations in non-BRCA genes and to see whether these mutations lead to different patient characteristics such as age of onset, race, tumor type, and how long patients live before cancer recurs or they die from their cancer. To determine this, we will examine genetic sequencing data from around 4,300 women with ovarian cancer that were all tested with a highly sensitive and accurate multiple-gene test called BROCA. BROCA is our in-house sequencing test that was developed in our laboratory and includes all known and suspected breast and ovarian cancer genes. We will compare mutation frequencies in this group to a control group of around 10,000 women who are over the age of 70, known to have not had breast or ovarian cancer, and are part of the Women’s Health Initiative (WHI) study. This comparison will help us identify what the risk of ovarian cancer is with mutations in these genes. The main advantage of our approach is that we have detailed clinical information about every woman with ovarian cancer; all women were enrolled at the time of cancer diagnosis without selecting them for young age or family history, and the two groups were sequenced using the same highly sensitive and accurate method. Having the clinical details will allow us to see whether different tumor types, ages, races, etc., make it more or less likely to have a mutation. Little is known about mutation frequency in African American women with ovarian cancer, and these women are often excluded from genomic studies due to lack of an appropriate control group. The WHI controls include a large number of African American women, allowing these comparisons to be made. One group of women with ovarian cancer comes from a clinical trial using a PARP inhibitor in combination with chemotherapy. We will also be able to do exploratory analyses to see whether mutations in non-BRCA genes make it more likely for a woman to respond to this type of drug. In summary, this proposal seeks to address the central problem of a lack of understanding of the risks of ovarian cancer and the implications for those with ovarian cancer for women with mutations in non-BRCA genes. We believe this information will allow more women to have the option of highly effective surgical prevention. As the information improves, more women will be tested, more will be offered surgery, and more ovarian cancers will be prevented. Considering that the vast majority of women with ovarian cancer d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910140
Entities
People
- Barbara Norquist
Organizations
- United States Army
- University of Washington