Sequencing the Next Generation of Glioblastomas

The most aggressive brain malignancy, glioblastoma, accounts for 60-70% of all gliomas and is uniformly fatal. According to the molecular signature, glioblastoma is divided into four subtypes (proneural, neural, classical, and mesenchymal), each with its own genetic background. The Cancer Genome Atlas project provides information about the most common genetic changes in glioblastoma. They involve mutations in TP53, TERT, and PTEN, and amplifications in EFGR, PDGFRA, CDK4, CDK6, MDM2, and MDM4. Recently, epigenetics was used to demonstrate the oncogenic roles of miR-124, miR-137, and miR-128. The most important findings so far are mutations in IDH1/2 and MGMT promoter methylation, which are routinely used as predictive biomarkers in patient care. Current clinical treatment leaves patients with only a 10% chance for 5-year survival. Attempts to define the mutational profile of glioblastoma to identify clinically relevant changes have not yet yielded significant results. This can be attributed to inter- and intra-tumor heterogeneity that is present in most glioblastomas, as well as hypermutation that appears as a consequence of chemotherapy. The evolving field of radiogenomics aims to classify glioblastoma using a combination of magnetic resonance imaging and genomic information. In the era of genomic medicine, next-generation sequencing is extensively used in glioblastoma research because it can detect multiple changes in a single biological sample; its potential in detecting circulating cell-free DNA has been tested in cerebrospinal fluid and plasma, and it shows promise in the examination of the cellular content of extracellular vesicles as a potential source of biomarkers. Next-generation sequencing is making its way into glioblastoma diagnostics. Gene panels like GlioSeq, which includes the most commonly mutated genes, are currently being tested on snap frozen and formalin fixed paraffin embedded tissues. This new methodology is helping to define the "next generation of glioblastomas" - clinically defined and better understood, with greater potential to improve patient care. However, limitations of the necessary infrastructure, space for data storage, technical expertise, and data ownership need to be considered carefully.