Hereditary X-Linked Tumor Suppressor Escapes Immune Control in Prostate Cancer
Abstract
There may be a genetic connection between prostate cancers and ovarian cancers: because fathers carry only one X-chromosome and this chromosome must pass to their daughters, we have previously shown that families with an unusual number of daughters with ovarian cancer also tend to have fathers with prostate cancers. Through DNA sequencing, we have found a candidate gene that lies near a previously identified candidate for prostate cancers. Therefore, one aim in our proposal is to identify families that have many prostate cancers to ascertain whether they also have ovarian cancers, and then to perform confirmation DNA sequencing of the X-chromosome. This aim will confirm the connection between the two diseases, may help identify cases of the disease that were previously thought to be sporadic, and may lead to a new risk factor marker for earlier monitoring and diagnosis. The particular region of the X-chromosome is also different (under selection) between European and African ancestries, implying that it may shed some light on why African American men are more often diagnosed with prostate cancer than European American men and why their prognosis is worse. Other researchers have also conjectured that the particular gene, MAGEC3, may be a tumor suppressor gene—a gatekeeper or caretaker gene that prevents cells from turning into cancer. Our proposal will directly test this hypothesis by modifying the level of the gene and looking for subsequent tumor-like behavior in an experimental system. If we observe this behavior, we will also take measurements that will help us deduce how MAGEC3 works with other genes to prevent tumors. We think this gene is similar to the better known BRCA1 and BRCA2 genes in that it may repair DNA damage, but we have also shown that it appears independently of these genes. MAGEC3 is therefore a good candidate to advance to genetic testing panels if our research hypothesis is confirmed. We will also study tumors banked at our institution and our collaborators’ institutions to understand how actual tumors use MAGEC3. In ovarian tumors, we have shown that MAGEC3-expressing tumors have a poor prognosis, and we have presented data to show that the immune system is less effective in these people. We expect that not every prostate tumor will have the gene, and it is important to understand whether these are more or less aggressive cases and whether the prognosis is better or worse. Ultimately, our goal is to improve the treatment of lethal prostate cancers. Our work will directly lead to potential therapies for this subtype of prostate cancer. If the DNA repair function is confirmed, there is good reason to use drugs called PARP inhibitors, and our gene may identify which patients specifically will benefit from treatment. If the immune suppression function is confirmed, cases that are MAGE-positive could be treated with immune checkpoint blockade drugs that reactivate the parts of the immune system that target MAGE. According to recent Department of Veterans Affairs studies, the Veteran population reflects the general U.S. population and, because cancer risk grows with age, it is expected that the burden of prostate cancer disease will rise. Understanding the origin and natural progression of these cancers will strengthen evidence for drug treatments or will help identify men who may not have a particularly aggressive disease may avoid radical surgery. Hereditary cancers are often early onset, so the variants under study may be directly relevant to current Service members. In addition, understanding the hereditary component of these MAGE-driven cancers may also assist families in early detection of other ovarian cancers. Therefore, our proposed project has a high potential to benefit the health and welfare of the aging Veteran population and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910397
Entities
People
- Kevin H Eng
Organizations
- United States Army