Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature

Abstract

Background and Objective Glioblastoma multiforme (GBM) is still a deadly disease with a poor prognosis and high mortality, despite the discovery of new biomarkers and new innovative targeted therapies. The role of genetic mutations in GBM is still not at all clear; however, molecular markers are an integral part of tumor assessment in modern neuro-oncology. Material and Methods We performed a Medline search for the key words “glioblastoma,” “glioblastoma multiforme,” and “genetic” or “genetics” from 1990 to the present, finding an exponential increase in the number of published articles, especially in the past 7 years. Results The understanding of molecular subtypes of gliomas recently led to a revision of the World Health Organization classification criteria for these tumors, introducing the concept of primary and secondary GBMs based on genetic alterations and gene or protein expression profiles. Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/2 mutations (50% of secondary GBMs), and also O6-methylguanine-DNA methyltransferase promoter methylation (75% of secondary GBMs). Conclusion From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM.

Construct ion of co - expression modules related to survival by WGCNA and identif ication of potential prognostic biomarkers in glioblastoma

“…The advances in GBM therapy have not concomitant with prominent amelioration in outcomes until recently [22]. Therefore, exploring molecular targets and therapeutic means are urged needed [23]. Years of molecular studies have identified many key links that affect the development and progression of GBM [24].…”

The Involvement of Exosomes in Glioblastoma Development, Diagnosis, Prognosis, and Treatment

“…The Cancer Genome Atlas has revolutionised research on the GBM genome by revealing different mutations in tumour suppressor genes and oncogenes specific to different GBM variants. This eliminates the inconvenience of histological assessment, which cannot always differentiate among the high heterogeneity of GBM [ 23 , 25 ]. Additionally, the same project described three major pathways that are usually involved in GBM pathogenesis—the tumour protein p53 (P53) pathway, the receptor tyrosine kinase/Ras/phosphoinositide 3-kinase (PI3K) signalling pathway and the retinoblastoma (RB) pathway—whose mutations lead to the excessive proliferation of tumour cells by augmenting cell lifespan via apoptosis inhibition and increasing the proliferation rate [ 24 ].…”

“…While similar mutations can be shared by both subgroups, their prevalence differs. Notably, GBM may acquire further molecular alterations over time [ 25 ].…”

“…However, the prognostic value of this mutation remains debatable: while some authors [ 28 ] associate EGFRvIII overexpression with poor survival, others [ 29 ] suggest it as a positive prognostic marker indicating an extended survival period when following the Stupp protocol [ 30 ]. Apart from being an important diagnostic marker, it represents a target for newly-developed EGFR-targeted therapies; however, the results have been disappointing to date, which is likely due to insufficient penetration of the blood–brain barrier [ 23 , 25 , 27 , 30 ]. PTEN normally inhibits the PI3K/AKT/mTOR pathway, one of the main molecular pathways involved in GBM expansion.…”

“…PTEN normally inhibits the PI3K/AKT/mTOR pathway, one of the main molecular pathways involved in GBM expansion. Consequently, its mutation supports excessive tumour proliferation [ 25 ]. TERT mutation activates telomerase, the key enzyme that prevents telomere shortening during repeated divisions, thereby supporting the excessive proliferation of cancer cells [ 30 ].…”