Epigenomic Master Regulators that Define IDH1/2 Mutant Glioma Tumor Progression
Abstract
Despite advances in surgical techniques and clinical regimens such as chemo- and radiotherapy, treatment of brain cancer around the world and among military personnel, Veterans, and their family members remains challenging and the tumor usually progresses or returns. Although environmental risk factors for brain cancer remain poorly defined, with the exception of exposure to ionizing radiation, evidence has shown that military and Veteran personnel exposed to traumatic brain injury are predisposed to brain cancer development via inflammation and stem cell transformation. Malignant glioma recurrence is a fast-growing disease and almost surely a sign of chemoresistance and an incurable tumor, with rare exceptions. Unfortunately, brain cancer can affect all age groups, and although young adults and children diagnosed with brain cancer may in some cases have good prognosis, there are some who do very poorly and do not respond to treatment. Therefore, understanding the mechanisms of brain cancer progression after treatment is essential and will have profound clinical implications in terms of management and differential diagnosis. Recently, evidence has shown that potential drivers of cancers are mediated not by gene mutation, but by epigenetics. DNA methylation is a biochemical reaction frequently found in cancer cells that prevents the activation of the gene next to it. It differs from genetic mutation, in which the change in the DNA chain occurs within the gene. Our group has studied DNA methylation in brain cancer, which led to discoveries about the presence and the combination of different molecular indicators that allow more accurate prediction of patients’ prognoses. We discovered low-grade and high-grade gliomas mixed together within these different epigenetic subtypes. This was an unexpected finding and allowed us to further understand the progression of gliomas within the different subtypes. By looking at the molecular makeup of these tumors, we now have a much more precise way of predicting which tumors are more likely to grow rapidly. These findings are an important step forward in our understanding of glioma as discrete disease subsets, and the mechanism driving glioma formation and progression. In our previous report, we observed a subgroup of young adults with brain cancer progresses to a more aggressive clinical phenotype and the epigenetic changes were found in areas of the genome not near a gene. These areas have been shown to be functionally important in regulating genes, sometimes megabases away or on different chromosomes from its target site. Evidence suggests that loss of DNA methylation at these elements may influence the regulatory network and could drive distinct phenotypes. The goal of this project is to test our hypothesis that changes of DNA methylation at these functional elements drives brain cancer progression. Validation of this hypothesis would have significant clinical implications, as it could lead to identification driver events not mediated by genetics but by epigenetics and that could serve as novel and effective therapeutic targets and potentially predictive biomarkers for brain cancer progression. Our hypothesis is based on our previous report of analyzing matched glioma samples, which revealed that 12% of a subclass of brain cancer cases progressed to a more aggressive clinical phenotype and the molecular changes occur at candidate functional elements, suggesting the existence of a potential master regulator affecting brain tumor progression in young adults. To test our findings, we will extract the molecular DNA and RNA from patients who progressed to an aggressive and nonaggressive phenotype. We will then apply high-throughput next-generation sequencing to map all epigenetic changes at the DNA level between these two groups in order to identify the master regulators driving the more aggressive phenotype. Results of this project will transform the way we approach th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810540
Entities
People
- Houtan Noushmehr
Organizations
- Henry Ford Health
- United States Army