Glioma epigenetics: From subclassification to novel treatment options

Abstract

Gliomas are the most common malignant primary brain tumors, of which glioblastoma is the most malignant form (WHO grade IV), and notorious for treatment resistance. Over the last decade mutations in epigenetic regulator genes have been identified as key drivers of subtypes of gliomas with distinct clinical features. Most characteristic are mutations in IDH1 or IDH2 in lower grade gliomas, and histone 3 mutations in pediatric high grade gliomas that are also associated with characteristic DNA methylation patterns. Furthermore, in adult glioblastoma patients epigenetic silencing of the DNA repair gene MGMT by promoter methylation is predictive for benefit from alkylating agent therapy. These epigenetic alterations are used as biomarkers and play a central role for classification of gliomas (WHO 2016) and treatment decisions. Here we review the pivotal role of epigenetic alterations in the etiology and biology of gliomas. We summarize the complex interactions between “driver” mutations, DNA methylation, histone post-translational modifications, and overall chromatin organization, and how they inform current efforts of testing epigenetic compounds and combinations in preclinical and clinical studies.

Introduction

Gliomas are among the most common primary brain tumors in adults and account for over 70% of malignant brain tumors, of which glioblastoma is the most common and most malignant (World Health Organization [WHO] grade IV) with an incidence rate of 3.2 per 100 000 population [1]. The median survival is less than 2 years with the current standard of care of maximal safe resection, followed by combined radio-chemotherapy with the alkylating agent Temozolomide [2] that may be modestly improved with the addition of Tumor Treating Fields [3]. Glioblastomas are notorious for resistance to therapy, and despite numerous efforts, the addition of targeted agents against genetic or biological hallmarks of gliomas have largely failed [4]. Lower grade gliomas (LGG) WHO grade II and III are less common and affect younger patients. They have a better prognosis and show some sensitivity to therapy that both depend on the molecular subtype [5], [6]. After resection LGG patients may first just be followed according to a “wait and see” strategy that depends on clinical and molecular risk factors, before entering treatment with different schemes of radio- or chemotherapy, or a combination thereof [6], [7], [8]. The optimal therapy is debated, however treatment related effects on cognitive function require risk-adapted (molecularly driven) treatment strategies, given that LGG patients may live more than 15 years [9].