Emerging Interplay of Genetics and Epigenetics in Gliomas: A New Hope for Targeted Therapy

Diffusely infiltrating gliomas are inherently heterogeneous tumors, and there are ongoing efforts to establish a classification scheme that incorporates new molecular and traditional histologic features. In less than a decade, high-throughput sequencing of gliomas has transformed the field, uncovering several pivotal, highly prevalent genetic alterations that stratify patients into different prognostic and treatment-response categories. We highlight the genetic aberrations recently discovered in isocitrate dehydrogenase, alpha thalassemia/mental retardation syndrome X-linked, death-domain–associated protein, histone H3.3, and telomerase reverse transcriptase and discuss how these mutations lead to unexpected changes in the epigenetic landscape in gliomas. We describe the opportunities these discoveries might provide for the development of novel targeted therapy aimed at reversing early epigenetic aberrations in glioma precursor cells. Finally, we discuss the challenges for effective treatment of this fatal disease posed by intratumoral heterogeneity and clonal evolution.