Diffuse gliomas are the most frequent brain tumor in adults. This group of brain neoplasms, ranging from histologically benign to aggressive malignant forms, represents a challenge in modern neurooncology because of the diffuse infiltrative growth pattern and the inherent tendency to relapse as a more malignant tumor. Once the disease achieves the stage of glioblastoma multiforme (GBM), the prognosis of patients is dismal and the median survival time is 15 months. Exhaustive genetic analyses have revealed a variety of deregulated genetic pathways involved in DNA repair, apoptosis, cell migration/adhesion, and cell cycle. Recently, investigation of epigenetic alterations in gliomas has contributed to depict the complexity of the molecular lesions leading to these malignancies. Even though, the efficacy of the state-of-the-art form of chemotherapy in malignant gliomas with temozolomide is based on the methylation-associated silencing of the DNA repair gene MGMT. Nevertheless, the whole scenario including global DNA hypomethylation, aberrant promoter hypermethylation, histone modification, chromatin states, and the role of noncoding RNAs in gliomas has only been partially revealed. We discuss the repercussion of epigenetic alterations underlying deregulated molecular pathways in the pathogenesis and evolution of gliomas and their impact on management of patients. 1. Introducing the Challenge: The Management of Gliomas Gliomas are the most frequent primary brain tumors in adults accounting for more than 70% of all brain neoplasms and display a group of tumors with different features regarding morphology, genetic and epigenetic aberrations, and response to therapy [1]. An additional relevant feature of gliomas represents its great tendency to infiltrate into adjacent normal brain tissue. The outer border of gliomas, as observed by T1-weighted magnet resonance imaging (MRI), does not delineate the true dimension of the tumor. Moreover, tumor cells diffusely invade the normal brain and can be detected far beyond rendering this condition incurable by combined surgery, radio, and chemotherapy (Figure 1). This is more true for glioblastoma multiforme (GBM), which accounts for about 60% of all gliomas and 12–15% of all brain tumors, and it is per se the most frequent primary brain tumor [1, 2]. It is one of the most devastating and lethal forms of human cancer despite the significant efforts that have been made to unravel its molecular basis. In Europe and North America, the incidence is three new cases per 100,000 inhabitants per year (Central Brain Tumor
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