Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

Abstract

Glioblastomas are the most frequent and malignant brain tumor hallmarked by an invariably poor prognosis. They have been classically differentiated into primary isocitrate dehydrogenase 1 or 2 (IDH1 -2) wild-type (wt) glioblastoma (GBM) and secondary IDH mutant GBM, with IDH wt GBMs being commonly associated with older age and poor prognosis. Recently, genetic analyses have been integrated with epigenetic investigations, strongly implementing typing and subtyping of brain tumors, including GBMs, and leading to the new WHO 2021 classification. GBM genomic and epigenomic profile influences evolution, resistance, and therapeutic responses. However, differently from other tumors, there is a wide gap between the refined GBM profiling and the limited therapeutic opportunities. In addition, the different oncogenes and tumor suppressor genes involved in glial cell transformation, the heterogeneous nature of cancer, and the restricted access of drugs due to the blood–brain barrier have limited clinical advancements. This review will summarize the more relevant genetic alterations found in GBMs and highlight their potential role as potential therapeutic targets.

Epigenetic alterations in glioblastomas: Diagnostic, prognostic and therapeutic relevance

“…Indeed, in this edition, several genetic and epigenetic biomarkers have been introduced to finely classify and subclassify gliomas. Among the new molecular parameters added to resolve doubtful cases, the presence of EGFR amplification, chromosome 7 amplification, loss of heterozygosity involving chromosome 10 and TERT promoter mutations have been associated with GBM diagnosis, although morphological features would often indicate a lower histological grading 1,2 . Thus, morphological features alone appear to be insufficient to settle GBM diagnosis.…”