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