Glioblastoma Genomics: A Very Complicated Story

Abstract

Glioblastoma is a deadly disease that has not shown improvement despite the development of new diagnostic tools and innovative targeted therapies. This grim outcome is mainly related to a complex intra-and inter-individual heterogeneity resulting from severe genetic instability. Understanding glioblastoma biology may establish a foundation to improve prophylaxis, early diagnosis, prognosis, and treatment prediction, thus leading to a better outcome. Recent advances in technologies such as genomics, epigenomics, transcriptomics, and proteomics have led to unprecedented discoveries of potential prognostic and predictive markers. Several of these biomarkers are in deep need of validation to be used in clinical routine. In this chapter, we will discuss the most accomplished recent advances in the genomics of glioblastoma and insight into personalized medicine using validated, and not yet validated, biomarkers that may have great potential to improve patients' outcomes.

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

“…12 In primary GBMs, the most frequent genetic alterations observed are loss of heterozygosity (LOH) at 10q (65% of cases), amplification or mutation of epidermal growth factor receptor (EGFR) (22-40%), amplification of platelet-derived growth factor receptor (PDGFR) (7%), tumor protein 53 (TP53) mutation (28-31%), cyclin-dependent kinase inhibitor 2 A/B (CDKN2A/B) deletion (31%), phosphatase and tensin homolog (PTEN) mutation or deletion (24-30%), IDH1/2 mutation (5%), telomerase reverse transcriptase (TERT) promoter (10%), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (36%), loss of expression of the retinoblastoma gene (RB1) (2%), phosphatidylinositol-4,5-bisphosphate 3-kinase A (PIK3CA) (1%), murine double minute 2 (MDM2) (7-12%), neurofibromatosis type 1 (NF1) deletion or mutations (11%), and glioma-associated oncogene homolog 1 (GLI1) (5-22%). 8,[13][14][15][16][17][18][19][20][21] In secondary GBMs, the most frequent genetic alteration observed are TP53 mutation (65% of cases), LOH at 22q (70-80%), LOH 19q (40-50%), IDH1/2 mutation (45-50%), MGMT promoter methylation (75%), CDKN2A/B deletion, PDGFR gene amplification (7%) 1p/19q codeletion (15-20%), and EGFR (5-7%). 16,17,20,[22][23][24][25][26]…”

“…8,[13][14][15][16][17][18][19][20][21] In secondary GBMs, the most frequent genetic alteration observed are TP53 mutation (65% of cases), LOH at 22q (70-80%), LOH 19q (40-50%), IDH1/2 mutation (45-50%), MGMT promoter methylation (75%), CDKN2A/B deletion, PDGFR gene amplification (7%) 1p/19q codeletion (15-20%), and EGFR (5-7%). 16,17,20,[22][23][24][25][26]…”

“…Some of them are currently considered clinically significant and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65% versus 28% of primary GBMs); IDH1/2 mutations (50% of secondary versus 5% of primary GBMs); and also MGMT promoter methylation (75% of secondary GBMs versus 36% of primary GBMs). 17,27 TP53 mutation is predominantly related to secondary GBMs, suggesting that TP53 mutation is a specific and stereotyped event in secondary GBM oncology, whereas TP53 mutation in primary GBM is potentially a consequence of widespread genomic instability. In 2008, Parsons et al first reported recurrent mutations in the IDH1/2 genes in patients with gliomas.…”

Rethinking Alkylating(-Like) Agents for Solid Tumor Management

“…High systemic toxicity of conventional anticancer agents can be overcome by using a more suited route of administration depending on the tumor type. In the case of operable patients with glioblastoma, an alternative to temozolomide relies on the implantation of carmustineloaded wafers (Gliadel ® ) within the resection cavity at the end of the surgery [42,43]. In such aqueous environment, the anhydride bonds of the biodegradable polymeric matrix get hydrolyzed, allowing for a controlled and sustained release of the drug that can diffuse within the surrounding parenchyma during several weeks.…”

“…In such aqueous environment, the anhydride bonds of the biodegradable polymeric matrix get hydrolyzed, allowing for a controlled and sustained release of the drug that can diffuse within the surrounding parenchyma during several weeks. After degradation, the active metabolite can alkylate DNA, cross-link with RNA and entail proteins carbamylation, ultimately leading to cell apoptosis [43]. Although Gliadel ® demonstrated a high therapeutic efficacy in animal models, clinical translation is limited by side effects and poor diffusion within the damaged [60,61].…”