Developing novel epigenetic biomarkers for predicting the prognosis and therapy-responses of glioblastomas

One of the major reasons for the poor prognosis of GBM is due to high tumor heterogeneity, wherein discrete subsets of GMB feature unique patterns of pathobiology and prognosis.3 Though several molecular markers have been found to have value in clinical diagnosis, prognosis and treatments, such as IDH1/2 mutations and the promoter methylation status of MGMT, further improvements in prognostic stratification and novel therapies are urgently needed. Recent research progress suggests a distinct role of 5hmC in gene regulation and various cellular processes including cancer development.13,21 In brain tumors, global 5hmC levels were found to be high in low-grade tumors and reduced in malignant GBM, but did not exhibit correlation with the known survival marker IDH1 mutation status.22 Moreover, nuclear exclusion of Tet1 was shown to be associated with loss of 5hmC in IDH1 wild-type gliomas29, while Tet1-mediated production of 5hmC was found to be required for the tumorigenicity of glioblastoma cells.23 Taken together, 5hmC has a great potential to be a novel epigenetic biomarker for the prognosis of GBM. However, to gain deeper insights into the epigenetic contributions to GBM and their prognosis, it is necessary to distinguish the two major types of cytosine modifications: 5hmC and 5mC, the latter of which has been the focus of previous studies due to technical limitations. In this project, we will address this urgent challenge by employing a novel epigenomic profiling approach to accurately distinguish 5hmC from 5mC at single base resolution, and assess their contributions to the prognosis of GBM. We hypothesize that 1) 5hmC, which is abundant in brain tissues, is associated with the prognosis of GBM; 2) an integrated index that combines both 5hmC and 5mC can be used to better predict the survival outcomes of patients with GBM. The success of this project will allow us to further advance the ultimate goal of realizing truly personalized medicine for people afflicted with GBM, therefore improving the care of brain cancer patients.