Molecular and Genomic Alterations in Glioblastoma Multiforme

Abstract

In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors.

The great imitator - EMA positive glioblastoma multiforme

“…GBM has been known to have a great variety of molecular types and subtypes, which have only very recently been demonstrated to be associated with different histomorphological forms of the tumor (21)(22)(23)(24)(25)(26)(27)(28). It is yet unknown whether these mutations would play a role in the IHC profile, but such a correlation does not seem unlikely.…”

The role of octamer binding transcription factors in glioblastoma multiforme

“…This subgroup is most prevalent in younger patients, and these tumors demonstrate global hyper-methylation, associated with IDH1 mutations and better survival [13, 15]. The mesenchymal subtype is defined by frequent mutations in the NF1 (in 37% cases), PTEN and TP53 tumor suppressor genes, whereas no distinctive mutations have been demonstrated in the neural subtype of GBMs [16]. Apart from these several gene mutation in GBM subtypes, adjuvant therapy with TMZ undoubtedly leaves an imprint in the genome evolution in low grade glioma.…”

PD-1 blockade enhances the vaccination-induced immune response in glioma

“…Glioblastoma (GBM) is a devastating disease, for which the diagnosis is associated with an extremely poor prognosis and median survival of 14 months following surgery, radiation, and chemotherapy (1–3). Our group and others have pioneered a DC vaccine–based immunotherapy platform, the results of which have suggested benefit in early-phase trials by promoting an endogenous antitumoral immune response (4–7).…”