Beyond Genetics in Glioma Pathways: The Ever-Increasing Crosstalk between Epigenomic and Genomic Events

Abstract

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.

Figure 1

(a)   T1-weighted, gadolinium-enhanced axial MRI showing the resection hole one day after surgical extirpation of a right frontal glioblastoma multiforme (1). Four months after surgery, fractionated radiotherapy (59 Gy), and chemotherapy with temozolomide, a new right periventricular tumor manifestation was observed invading the basal ganglia. An enhancement in the dorsal resection hole is evidenced, also indicating the local relapse (2). MRI gently provided by Professor A. Giese (Department of Neurosurgery, University of Mainz, Germany). (b) T1-weighted, gadolinium-enhanced axial MRI revealing a large left frontal glioblastoma. The illustration depicts the outer tumor border (as defined by the gadolinium enhancement) with glioblastoma cells migrating far away through the brain tissue.

Figure 2

TP53/MDM2/p14^ARF and cell cycle p16^INK4a/CDK4/RB1 networks and targets of hypermethylation-mediated inactivation (marked by red stocks).

Figure 3

(a) 3D MRI. Normal glial cells CpG islands in the promoter regions of genes lack of methylation, which is a prerequisite for active gene transcription. Fully methylated CpG islands are found only in the promoters of silenced alleles for selected imprinted autosomal genes and silenced genes on the inactivated X-chromosomes of females. (b) 3D MRI showing a right frontal GBM, in which cells change their methylation pattern in a wide manner including deregulation of methylating DNA methyl-transferases 1, 3A, and 3B, global hypomethylation through demethylation in CpG islands of the promoters of a wide variety of genes as well as a severe hypermethylation locally affecting unmethylated regions. Densely methylated DNA is associated with deacetylated histones and compacted chromatin, which is refractory to gene transcription.

Figure 4

Diagram showing how alkylating drugs temozolomide (TMZ), nimustine (ACNU), and carmustine (BCNU) act damaging DNA by introducing alkyl residues in the O⁶ position of guanine, thus producing DNA interstrand cross-links. The DNA repair O⁶-methylguanine DNA methyltransferase (MGMT) reverses the formation of adducts at the O⁶ position of guanine. MGMT transfers the alkyl group from the O⁶-guanine to an active cysteine within its own sequence in a reaction that inactivates one MGMT molecule for each lesion repaired. The alkylated MGMT protein then becomes detached from DNA and is targeted for degradation by ubiquitination.