Genetic Alterations in Glioblastoma and Their Clinical Implications – A Comprehensive Review

1. Introduction

Glioblastoma (GBM) is the most aggressive primary brain tumor with limited treatment options and poor prognosis (1). Despite advancements in surgical techniques, radiation therapy, and systemic therapy, such as the addition of tumor-treating fields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, remains dismal in terms of median survival of GBM patients (2). In recent years, molecular research has provided valuable insights into the underlying mechanisms of GBM, uncovering key molecular alterations and signaling pathways that drive tumor development and progression. Understanding these molecular advances holds great promise for developing targeted therapies and improved clinical outcomes for GBM patients.

One of the major advancements in GBM research has been the identification of driver mutations that contribute to tumor initiation and progression (3). The dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway has also emerged as a significant molecular alteration in GBM. EGFR alterations, including gene amplification and mutations, are frequently observed and play a critical role in promoting tumor growth, invasion, and therapy resistance (4).

Epigenetic modifications, including deoxyribonucleic acid (DNA) methylation and histone modifications, have been recognized as important contributors to GBM pathogenesis (5). Additionally, non-coding ribonucleic acids (RNAs), such as microRNAs and long noncoding RNAs, have been implicated in GBM biology, functioning as regulators of gene expression and potential therapeutic targets (6).

The interaction between GBM and the immune system has led to the exploration of different strategies for immunotherapeutic treatments that can lead to a better prognosis for patients with glioblastoma (7).

The purpose of this literature review is to summarize and emphasize the significance of molecular advances in glioblastoma research.

2. Discussion

2.1. Driver Mutations

Driver mutations play a critical role in the pathogenesis of glioblastoma (GBM), influencing tumor initiation, growth, and therapeutic response. The mutation of the epidermal growth factor receptor (EGFR) gene is a key driver mutation identified in GBM with significant functional significance, impacting the prognosis, and with potential therapeutic implications.

Mutations in the epidermal growth factor receptor (EGFR) gene are the most frequently observed genetic alterations in GBM, occurring in approximately 50% of cases (8). EGFR alterations include gene amplification, point mutations (e.g., EGFRvIII), and other structural alterations, leading to constitutive activation of the EGFR signaling pathway (9). EGFR alterations contribute to tumor growth, invasion, and therapy resistance through various mechanisms, including enhanced cell proliferation, survival signaling, angiogenesis, and immunosuppression (3). EGFRvIII, a common EGFR variant, is particularly prevalent in GBM and has been associated with a more aggressive phenotype (10). EGFR alterations have prognostic implications, with EGFR amplification and EGFRvIII associated with worse overall survival (11). Targeting EGFR alterations has been a major focus of therapeutic development in GBM. Multiple approaches, including small molecule inhibitors, monoclonal antibodies, and immunotherapies, have been explored in clinical trials, but no EGFR-targeted strategy has been proven efficient in GBM (12).

2.2. Dysregulated Signaling Pathways

The phosphoinositide 3-kinase/proteinkinase B/mammalian (or mechanistic) target of the rapamycin (PI3K/Akt/mTOR) pathway is frequently dysregulated in GBM, promoting cell survival, proliferation, and angiogenesis (13). Activation of this pathway occurs through various mechanisms, including genetic alterations, such as mutations in the PI3K catalytic subunit (PIK3CA) or the loss of phosphatase and tensin homolog (PTEN) tumor suppressor function (14). Therapeutic targeting of the PI3K/Akt/mTOR pathway has shown promise in preclinical models and earlyphase clinical trials. Inhibitors of PI3K, Akt, and mTOR have been developed and tested, either as single agents or in combination with other therapies. However, challenges such as intrinsic and acquired resistance mechanisms, complex feedback loops, and the presence of multiple isoforms within the pathway have limited the success of targeting this pathway in GBM (15). Combination strategies and personalized approaches based on individual pathway alterations may hold promise for improving therapeutic outcomes.

The rat sarcoma virus/ rapidly accelerated fibrosarcoma/ mitogen-activated protein kinase/ extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) pathway is another dysregulated signaling cascade implicated in GBM. Aberrant activation of this pathway occurs through genetic alterations, including amplification or mutations in the epidermal growth factor receptor (EGFR) gene or downstream components of the pathway (16). The Ras/Raf/MEK/ERK pathway regulates cell proliferation, survival, and invasion in GBM. Efforts to target this pathway in GBM have faced challenges due to the complexity of pathway crosstalk, adaptive resistance mechanisms, and the lack of potent and selective inhibitors (17). Clinical trials exploring combination therapies targeting multiple nodes within the pathway or combining pathway inhibitors with other treatment modalities are ongoing, aiming to enhance therapeutic efficacy.

The neurogenic locus (NOTCH) signaling pathway plays a critical role in GBM stem cell maintenance, tumor angiogenesis, and immune modulation (18). Dysregulation of NOTCH pathway components, including NOTCH receptors and ligands, is observed in GBM. Aberrant activation of NOTCH signaling contributes to tumor growth and therapy resistance (19). Therapeutic targeting of the NOTCH pathway in GBM has been challenging, with limited success in clinical trials. Complex cross-talk with other signaling pathways, the presence of multiple NOTCH receptors, and the context-dependent effects of NOTCH signaling pose hurdles in developing effective targeted therapies (20). However, the development of novel approaches, such as gamma-secretase inhibitors and antibody-based therapies, holds promise for future therapeutic interventions.

2.3. Epigenetic Modifications

DNA methylation is a key epigenetic modification that regulates gene expression. In GBM, global DNA hypomethylation and sitespecific hypermethylation are commonly observed. Promoter hypermethylation leads to the silencing of tumor suppressor genes, contributing to tumor initiation and progression (21). For example, the methylation of the O^6 methylguanine-DNA methyltransferase (MGMT) gene promoter is associated with increased sensitivity to alkylating agents, such as temozolomide (22). Other genes involved in cell cycle control, DNA repair, and apoptosis are also frequently hypermethylated in GBM (5). DNA methylation profiles have been utilized for molecular classification and prognostication of GBM patients, providing valuable insights into tumor biology (23).

Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are emerging as key regulators of gene expression and GBM pathogenesis. miRNAs function as post-transcriptional regulators, modulating the expression of target genes. Dysregulation of specific miRNAs in GBM has been linked to tumor growth, invasion, angiogenesis, and therapy resistance (24). These miRNAs can act as oncogenes (oncomiRs) or tumor suppressors, depending on their target genes and downstream signaling pathways. Strategies to restore or inhibit specific miRNAs hold therapeutic potential in GBM treatment (25). Micro-RNAs (miRNAs) are differentially modulated in M059J and M059K cells exposed to ionizing radiation and so miRNA modulation contributes to the resistance to ionizing radiation. (26) Similarly, dysregulation of lncRNAs has been implicated in GBM biology, influencing tumor growth, invasion, and therapy response (27). The role of lncRNA HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) as a driver of biological aggressiveness, radioresistance, and poor outcome in glioblastoma has been demonstrated in recent studies. (28) Targeting specific lncRNAs may provide novel therapeutic opportunities for GBM patients.

The dysregulation of epigenetic modifications in GBM presents opportunities for the development of targeted therapies. Epigenetic modifiers, such as DNA methyltransferase inhibitors (DNMTi) and HDAC inhibitors, have been investigated in preclinical and clinical settings for GBM treatment. DNMTi, including 5-azacytidine and decitabine, can reverse aberrant DNA methylation patterns, reactivating silenced tumor suppressor genes (29). HDAC inhibitors, such as vorinostat and panobinostat, induce histone acetylation and promote gene expression changes (30). Altered expression/activity of key epigenetic regulators, especially histone deacetylases (HDACs) in GBM stem cells has been associated with poor prognosis; inhibiting the activity of HDACs using histone deacetylase inhibitors (HDACi) has been promising as mono-therapeutic in targeting GBM and in sensitizing GBM stem cells to an existing anticancer regimen (31). Combining epigenetic modifiers with other treatment modalities, such as chemotherapy or immunotherapy, holds promise for synergistic effects and improved outcomes (32). Furthermore, targeted therapies specific to dysregulated miRNAs and lncRNAs are being explored as potential interventions (33).

2.4. Immune Dysregulation

Immune checkpoint dysregulation is a key mechanism employed by GBM to evade immune surveillance. Immune checkpoints, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), regulate immune responses and maintain immune homeostasis. In GBM, these checkpoints are upregulated, leading to T-cell exhaustion and impaired antitumor immune responses (34). Targeting immune checkpoints (TAMs) using checkpoint inhibitors has shown promising results in various malignancies, leading to the restoration of Tcell function and enhanced antitumor immune responses (35). Checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 antibodies, aim to unleash the antitumor immune response by blocking immune checkpoint pathways and reinvigorating T-cell activity (36). CAR T-cell

therapy involves genetically engineering patients’ own T cells to express receptors specific to tumor antigens, enhancing their tumor recognition and killing abilities (37).

TAMs, which include macrophages and microglia, are major components of the immune infiltrate in GBM. TAMs have distinct polarization states, with the M2-like phenotype being predominant in GBM. M2-like TAMs exhibit immunosuppressive functions and promote tumor growth, angiogenesis, and invasion (38). The interaction between TAMs and GBM cells creates an immunosuppressive microenvironment that inhibits effective antitumor immune responses. Targeting TAMs and reprogramming them towards an M1-like phenotype, which exhibits antitumor activity, represents a potential therapeutic strategy (39).

The tumor microenvironment in GBM is characterized by immunosuppressive factors and signaling pathways that promote immune evasion. Immunosuppressive factors, such as transforming growth factor-β (TGF-β), interleukin-10 (IL-10), and indoleamine 2,3-dioxygenase (IDO), inhibit immune cell function and promote tumor tolerance (40). Additionally, GBM cells release factors that attract immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), further contributing to immune suppression (41).

Despite the promise of immunotherapy, several challenges exist in applying these approaches to GBM. The limited infiltration of immune cells into the tumor poses hurdles to effective immunotherapy delivery and efficacy (42). Overcoming these challenges requires the development of innovative strategies, such as local delivery methods, combination therapies, and the use of immune modulators to overcome immune suppression and enhance the therapeutic response (43).

2.5. Precision Medicine and Molecular Classification

The 2021 WHO classification adds several newly recognized tumor types and makes several important changes to principles relating to nomenclature, grading, and classification of CNS tumors, many of these changes increase the reliance on molecular alterations for disease classification and elevate the importance of molecular testing in diagnosis, treatment and prognosis (gliomas including glioblastoma, IDH-mutant astrocytic gliomas encompassing astrocytomas and oligodendroglioma, ependymomas and meningiomas). In the current classification, all IDH-mutant diffuse astrocytic tumors are considered a single type (Astrocytoma, IDHmutant) and are then graded as CNS WHO grade 2, 3, or 4. Glioblastoma, IDH-wildtype should be diagnosed in the setting of an IDHwildtype diffuse and astrocytic glioma in adults if there is microvascular proliferation or necrosis or TERT promoter mutation or EGFR gene amplification or +7/−10 chromosome copy number changes (44,45).

One of the most influential molecular classification efforts in GBM is The Cancer Genome Atlas (TCGA) project. The TCGA classification stratifies GBM into several distinct molecular subtypes based on comprehensive genomic and transcriptomic analyses (3). These subtypes include classical, mesenchymal, proneural, and neural subtypes, each characterized by specific molecular features and signaling pathway dysregulations. For instance, the classical subtype is associated with alterations in the epidermal growth factor receptor (EGFR) pathway, while the mesenchymal subtype shows enrichment for immune response-related genes and mesenchymal markers (23).

The molecular classification systems, such as the TCGA classification, have provided a more refined understanding of GBM biology and have important implications for personalized treatment strategies. By identifying specific molecular alterations within subgroups of GBM, these classification systems enable the development of targeted therapies aimed at disrupting the dysregulated signaling pathways unique to each subtype. For instance, EGFR inhibitors, such as erlotinib and gefitinib, have shown potential efficacy specifically in GBM patients with EGFR amplification or mutations (3).

Molecular classification also plays a crucial role in guiding the design of clinical trials for GBM. By considering the molecular characteristics of the tumor, clinical trials can be designed to specifically target and evaluate novel therapies in patients with specific molecular subtypes. This approach allows for more precise patient selection and potentially improves the chances of therapeutic success. For example, clinical trials may focus on evaluating immune checkpoint inhibitors in patients with the mesenchymal subtype, which is associated with immune response-related gene expression and may be more responsive to immunotherapy (46). By tailoring clinical trials based on molecular subtypes, researchers can better assess treatment efficacy and response rates within specific patient populations.

In addition to guiding treatment strategies and clinical trial design, molecular classification systems in GBM also hold promise in predicting treatment response. The identification of molecular subtypes associated with distinct clinical outcomes can aid in patient risk stratification and inform treatment decisions. For instance, the proneural subtype, characterized by IDH mutations, is associated with a better prognosis and may require less aggressive treatment compared to other subtypes (5).

2.6. Future perspectives

Future perspectives in molecular advances for glioblastoma present exciting opportunities for improved diagnosis, treatment, and patient outcomes. The identification of novel molecular targets holds the potential to develop more effective therapies tailored to individual patients. With advancements in genomic profiling, precision medicine approaches will become more commonplace, allowing for personalized treatment strategies based on the molecular characteristics of each patient’s tumor. Additionally, the integration of artificial intelligence and machine learning algorithms will enhance the analysis of large-scale molecular data, leading to improved prognostic models and treatment predictions. Furthermore, ongoing research on immunotherapies, including immune checkpoint inhibitors and CAR-T cell therapy, offers promising avenues for targeting the immune system to fight glioblastoma, for example, adding an autologous tumor lysatepulsed dendritic cell vaccine to standard therapy is feasible and safe in glioblastoma patients, and may extend survival (47).

Combination therapies that target multiple molecular pathways simultaneously are also being explored, aiming to overcome tumor heterogeneity and resistance mechanisms. Collaborative efforts among researchers, clinicians, and industry partners will be vital in translating these molecular advances into clinical practice, ultimately improving the prognosis and quality of life for glioblastoma patients in the future.

3. Conclusions

The recent molecular advances in GBM research have provided deeper insights into the underlying mechanisms driving tumor development and progression. The identification of driver mutations including the epidermal growth factor receptor (EGFR) gene, dysregulated PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, the NOTCH signaling pathways, epigenetic modification as DNA hypomethylation, and noncoding RNAs, and immune dysregulation, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has opened up new avenues for targeted therapies and immunotherapeutic approaches. These molecular advancements hold great potential for personalized treatment strategies, designed clinical trials to specifically target and evaluate novel therapies in patients with specific molecular subtypes, and also improving the prognosis and outcomes for GBM patients, offering hope for a brighter future in the management of this devastating disease.

Abbreviations:

GBM – Glioblastoma

EGFR – Epidermal growth factor receptor

PI3K/Akt/mTOR – Phosphoinositide 3-kinase/protein-kinase B/mammalian (or mechanistic) target of the rapamycin

Ras/Raf/MEK/ERK – Rat sarcoma virus/ rapidly accelerated fibrosarcoma/ mitogen-activated protein kinase/ extracellular signal-regulated kinase

α-KG – Isocitrate to α-ketoglutarate

TCA – Tricarboxylic acid cycle

2-HG – 2-hydroxyglutarate

PI3KCA – PI3K catalytic subunit

PTEN – Phosphatase and tensin homolog tumor suppressor

MGMT – O^6-methylguanine-DNA methyltransferase

HDACs – Histone deacetylases

PRC2 – Polycomb repressive complex 2

miRNAs – microRNAs

lncRNAs – Long non-coding RNAs

HOTAIRM1 – lncRNA HOXA transcript antisense RNA myeloid-specific 1

DNMTi – DNA methyltransferase inhibitors

PD-1 – Programmed cell death protein 1

CTLA-4 – Cytotoxic T-lymphocyte-associated protein 4

TGF-β – Transforming growth factor-β (TGF-β)

IL-10 – Interleukin-10

IDO – Indoleamine 2,3-dioxygenase (IDO),

Tregs – Regulatory T cells

MDSCs – Myeloid-derived suppressor cells

CAR – Chimeric antigen receptor

TCGA – The Cancer Genome Atlas

Statements:

Authors’ contributions: AG, and AN conceived and planned the review; GIE, SA, GT, and DME wrote the manuscript, AG reviewed the manuscript and made the final approval. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors.

Conflict of interests: The authors declare no conflict of interest.

Funding Sources: None

Statement of Ethics: The manuscript does not contain any studies carried out by the authors

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