Validation of Novel Drivers of Juvenile Polyposis Syndrome
Abstract
This application will address the Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Colorectal Cancer and Pediatric/Adolescent/Young Adult Cancer. It will also address the PRCRP Military Health Focus Area: Gaps in Cancer Research That May Affect Mission Readiness. Juvenile Polyposis Syndrome (JPS) is a cancer predisposition syndrome that is usually diagnosed in childhood, with polyps developing in the gastrointestinal tract (stomach and colon). These polyps are also associated with up to 50% risk of cancer lifelong. That cancer risk can be decreased by close surveillance with endoscopy and colonoscopy and removal of polyps. In some patients with JPS, there is a genetic cause of the polyps that is passed down in families (this is called mutation-positive JPS). The two genes that are known to cause JPS are BMPR1A and SMAD4. In the majority of patients, the genetic cause is not known (mutation-negative JPS). Our group has shown that for patients with mutation-negative JPS, there is a clear difference in features of the disease (phenotype). This includes fewer polyps as patients get older, a younger age at diagnosis of JPS, and polyps mainly in the colon (not in the stomach). This tells us that there is a difference in these patients, which suggests that there is a different reason that they develop JPS. However, without a genetic cause, it is difficult to understand their cancer risk, and it requires surveillance of all of their Family Members, including parents, siblings, and children. We have investigated the cause of polyps in these patients and have found that in a little under half (40%), there is a mutation that might cause their polyps; however, to prove that those mutations are related, we will need to conduct studies in colon organoids, which are three-dimensional cell structures that mimic the human colon. Dr. Lengner will develop these organoids in his lab and knock down (remove) or introduce specific mutations into the genes that we suspect cause JPS. We will then study the phenotype of gene-edited organoids relative to isogenic normal organoids and those carrying known JPS mutations. These studies will determine whether newly identified candidate genes contribute to polyp growth and may be causative of JPS. At the same time, Dr. MacFarland will use her large bank of patient samples, that have been collected in conjunction with her polyposis clinic to understand what other genetic changes might lead to JPS. This includes changes in the genetics of cells that are just in the colon (called mosaicism), or changes in the factors that tell cells to express those genes (called epigenetic changes). This will involve specialized genetic studies on a large number of samples, including comparing samples from both the colon and the polyps for each individual. Relevance to Intent: Through this work, we hope to improve our ability to treat patients with mutation-negative JPS - improving our ability to conduct cancer surveillance, and to know how to treat their Family Members, and which of their Family Members are at risk for cancer. Additionally, understanding the genetic cause of JPS will have implications for all patients with gastric and colorectal cancer, because the genetic changes in JPS are the first step in the development of cancer. Thus, this may suggest the cellular pathways that might be targeted in treatment of both polyposis and cancer. This will address the fiscal year 2022 PRCRP Overarching Challenge in Diagnostics/Prognostics: distinguish unique features driving cancer occurrence across the spectrum of ages. For both pediatric and adult JPS patients, as well as their Family Members, a better understanding of JPS genetics will help us to understand their cancer risk and potentially suggest new strategies of cancer prevention and treatment. This will be relevant to active-duty Service Members and their Families who are affected by JPS, helping them to understand their
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310786
Entities
People
- Christopher Lengner
Organizations
- United States Army
- University of Pennsylvania