Epigenetic Mechanisms of Tumor Initiation and Evolution

Bradley E. Bernstein, MD, PhD, Massachusetts General Hospital, Harvard Medical School

The importance of epigenetic regulation in cancer is now well established by a convergence of data from cancer genome sequencing, epigenomics, and the transcriptional and molecular characterization of tumors and models. Our laboratory is focused on characterizing epigenetic mechanisms of tumor initiation as well as on understanding how epigenetic changes and intratumoral heterogeneity contribute to drug resistance and tumor relapse. We have focused in particular on brain tumors as clinically compelling models for investigating epigenetic mechanisms of tumorigenesis. I will present two ongoing projects in this area. The first project is focused on genetic mutations that affect epigenetic regulators and processes and are associated with gliomagenesis. Here I will discuss our progress toward delineating specific mechanisms, regulatory targets, and programs that explain the tumorigenicity of individual mutations. The second project is focused on epigenetic mechanisms that enable glioblastoma stem cells to adapt to environmental stressors or drug pressures. Here we have identified a specific role for histone demethylases in resetting the epigenetic landscapes of glioblastoma stem cells, thereby allowing them to transition to a more primitive and refractory state. These respective studies exemplify ongoing research in our laboratory as well as in the broader research community and have general relevance for cancer biology, diagnosis, and therapy.