Integrative epigenomic analysis of gliomas: defining regulatory regions associated with stemness and with the hypermethylator phenotype of IDH1/2 mutant tumors

Abstract

Adult malignant Gliomas are heterogeneous brain tumors characterized by recurrence and progression with variable patterns. Although some progress has been seen in the past years, Glioma field faces suboptimal disease classification, which may impact patient management and hinder the correct treatment. Mutation in the IDH genes, the hypermethylator G-CIMP phenotype and codeletion of chromosome arms 1p/19q are associated with subtypes of Gliomas and improve their classification. Notably, increasing evidence suggests that aberrant DNA methylation play a role in the development and/or progression of Gliomas. In glioblastomas, it is appreciated that differentiation status impacts tumor cell properties and that stem-like cells likely drive tumor progression and therapeutic resistance. We aim to perform a comprehensive and integrated epigenomic analysis to define the regulatory regions associated with stemness in Gliomas and with the hypermethylator phenotype of IDH1/2 mutation in Gliomas and across different tumor types. Our findings may provide: 1) elucidation of the mechanisms of tumorigenesis and tumor progression; 2) potential mechanisms related to the genome-wide DNA methylation and metabolism dysregulation in IDH1/2 mutant tumors; and 3) potential translational outcomes, such as identification of biomarkers that predict for progression and drug resistance, novel targets for drug development, refinement of existing molecular tumor classification allowing a better stratification for tailored treatment. Finally, this proposal will establish the innovative area of cancer epigenomics at FCFRP, which will allow important collaboration and contribute to expanding the research actions at FCFRP. (AU)