Novel Tumor Suppressor Gene in Hereditary X-Linked Ovarian Cancers
Abstract
Ovarian cancers are too frequently diagnosed at an advanced stage due to the lack of early warning markers. A family history of ovarian cancer and/or breast cancer among female relatives remains one of the strongest known risk factors for ovarian cancer. Many women are familiar with the BRCA1 and BRCA2 genes, which are thought to account for up to 50% of inherited cases. This means that the remaining cancers may be due to missing genes, other family lifestyle factors, or just random chance. If we can find these missing genes, we will be better able to warn women about increased risk in a time period where they can receive counseling and explore preventative options. The search for missing ovarian cancer genes is the focus of our international collaborations and studies interviewing families with a significant number of cases of ovarian cancer with and without breast cancer. While most women with ovarian cancer do not have a family history of disease, our research has shown that we may have been looking in the wrong place: obviously, fathers do not develop ovarian cancer, but they can still pass genes that may cause cancer to their daughters. Our data suggests that there is a gene is on the X-chromosome and, because fathers only have one of these chromosomes, they must pass this risk gene to every one of their daughters. This may account for the increased rate of cancers among sisters, especially when their mother did not have ovarian cancer. We have worked with the largest and oldest collection of families with significant numbers of ovarian cancers to collect DNA to search for this gene. Our study uncovered a potential hit in a gene called MAGEC3 whose function is totally unknown. Based on our work so far, we believe that MAGEC3 is a tumor suppressor gene that normally functions to prevent cancer from growing. Women in our studies carried a mutant form of MAGEC3 and developed cancer almost a decade earlier than other women with a family history of ovarian cancer. Similar to how the BRCA genes were identified, verified, and characterized, our proposed research plan is to first study more family-based cases to determine how MAGEC3 loses its ability to suppress cancer. In parallel, we will experimentally add and subtract MAGEC3 from model ovarian cancer cell lines to see whether the gene slows tumor growth. We will validate positive findings in animal models by testing whether MAGEC3 expressing cell lines are more likely to form tumors. If this program is successful, MAGEC3 will be a strong candidate to add to genetic testing panels. More work in the short term will be required to figure out which specific mutations are important, but in the intermediate and long term these panels should augment the ability of clinical geneticists to identify families at risk from ovarian cancer. In addition, understanding how these genes cause cancer opens the door for new therapies: understanding the BRCA genes was an important part of the recently approved PARP treatments and BRCA status determines who is eligible for these drugs. The Department of Veterans Affairs reports that women comprise 20% of new recruits, 14% of the active military (2010), that there are 1.13 million women Veterans over the age of 50, and estimates that women will account for 10% of the Veteran population in 2018, increasing to 18% by 2040. Ovarian cancer rates among military Service members and their families are similar to the US civilian population. Importantly, genetically inherited cancers are often early onset (below age 45 for our studies) so our proposed program will have a strong potential to affect the health and welfare of women in the military and their families. Moreover, as in the case with the BRCA genes, the MAGEC3 gene may also be involved in male cancers such as prostate cancer, expanding the military population that would benefit from this research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810134
Entities
People
- Kevin H Eng
Organizations
- United States Army