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IJMSInternational Journal of Molecular Sciences
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28 May 2026

47 Pages

Brain Cancer: Molecular Alterations and Emerging Trends in Neuropharmacology

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Department of Pharmacology, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, 040 01 Kosice, Slovakia
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Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
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Department of Pathology, Faculty of Medicine, Pavol Jozef Safarik University in Kosice, 040 01 Kosice, Slovakia
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Department of Medical Pharmacology, School of Medicine, Health Sciences University, 34668 Istanbul, Türkiye
Int. J. Mol. Sci.2026, 27(11), 4880;https://doi.org/10.3390/ijms27114880
This article belongs to the Special Issue Precision Targets for Brain Health: The Molecular Era of Neuropharmacology
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Abstract

Central nervous system (CNS) tumors represent a heterogeneous group of neoplasms associated with significant morbidity and mortality despite their relatively low incidence. Advances in the fifth edition of the World Health Organization (WHO) classification have emphasized the integration of histopathological, immunohistochemical, and molecular features, fundamentally transforming diagnostic and prognostic frameworks in neuro-oncology. This manuscript aims to provide an overview of CNS tumor biology, focusing on key diagnostic markers, genetic and epigenetic alterations, and emerging therapeutic strategies. It further describes recent advances in multi-omics approaches and artificial intelligence, which enable deeper characterization of tumor heterogeneity and support the development of precision medicine strategies. Finally, current and emerging therapeutic modalities, including combination therapies, targeted treatments, and novel molecular targets, are examined with emphasis on overcoming resistance mechanisms and improving clinical outcomes. Overall, the integration of molecular biology, advanced diagnostics, and innovative therapeutic approaches represents a critical step toward personalized management of CNS tumors and improved patient survival.

1. Introduction

Central nervous system (CNS) tumors originate in different cell types and account for approximately 2% of all cancers. CNS tumors, particularly glioblastoma (GBM), IDH-wildtype, a CNS WHO grade 4 adult-type diffuse glioma, which represents the most common malignant primary brain and other CNS tumor in adults, represent a profound clinical challenge with a high mortality rate and a survival of 2.6%.While traditional epidemiological data heavily rely on older cohorts, large-scale genomic studies, including The Cancer Genome Atlas (TCGA)-derived analyses, have confirmed that survival remains poor despite multimodal treatment regimens.
The age-adjusted incidence rate was 3.5 per 100,000 people, with the highest rates observed in Southern and Western Europe [1]. Of these, primary brain tumors account for approximately 95% of CNS tumors [2]. These tumors represent a heterogeneous group and are stratified into distinct malignancy grades according to the World Health Organization (WHO) classification criteria. There are over 100 types of primary CNS tumors listed by the WHO International Classification of Diseases Oncology, and no dominant risk factor has been identified [3]. Malignant brain tumor incidence is highest in populations of predominantly European ancestry and in individuals with higher socioeconomic status [4].
CNS tumors are the most common cancer in children aged 0–14 years old and the second most common in 15–19 years old [5]. The incidence is highest for 5-year-olds and younger. The majority represent malignant tumors, especially gliomas, embryonal tumors, and germ cell tumors; the most common tumors of the pituitary gland are benign. Despite the high incidence and clinical significance of these tumors, their underlying etiology remains poorly understood [6]. To date, only two major risk factors have been consistently recognized: single-gene inherited disorders, for which available evidence remains limited due to the small number of studies conducted, and exposure to ionizing radiation, which demonstrates a well-established dose–response relationship [5]. In addition, several emerging factors warrant further investigation, including birth weight, as current evidence suggests that higher birth weight may be associated with an increased risk of CNS tumors, as well as non-chromosomal structural birth defects affecting the nervous system [5].
In adults, CNS tumors are the 8th most common cancer [7]. The majority of them are non-malignant, mainly meningioma and tumors of the pituitary gland; among malignant tumors, the most common are gliomas [5]. Despite extensive investigation into potential environmental contributors, high-dose ionizing radiation remains the only consistently established environmental risk factor. Many other risk factors are under investigation, for example, the use of mobile phones with their radiofrequency field, and low-frequency magnetic fields or power lines. However, no significant association emerged between the mentioned factors and risk of any type of brain tumor [8]. Instead, only limited data are available about infectious agents, namely the polyomavirus family [9] and protozoan Toxoplasma gondii [10]. On the contrary, an inverse association between previous varicella-zoster virus infection and glioma risk has been reported, potentially reflecting immune-mediated mechanisms. [11]. The same pathomechanism is hypothesized in allergies, reducing glioma risk. Some of the patients with brain cancer have a family history of brain tumors. Several hereditary cancer syndromes are associated with an increased risk of brain tumors, including neurofibromatosis types 1 and 2, tuberous sclerosis complex, and Li-Fraumeni syndrome. Typically, mutated genes in brain tumors are isocitrate dehydrogenase 1 and 2 (IDH1/2), telomerase reverse transcriptase (TERT), epidermal growth factor receptor (EGFR), and cyclin-dependent kinase inhibitor 2A (CDKN2A). All these mutated genes are found mainly in various types of gliomas [5].
This review argues that the current management of CNS tumors is moving from a morphology-centered framework toward a dynamic, multi-layered model in which histology, molecular profiling, spatial heterogeneity, therapeutic vulnerabilities, and computational tools are interpreted together. However, diagnostic markers are not always robust, molecular classifications are rapidly evolving, and many innovative therapeutic strategies remain highly limited by blood-brain barrier (BBB) penetration, intratumoral heterogeneity, and incomplete clinical validation.

2. Classification and Immunohistochemical Features of CNS Tumors

2.1. WHO 2021 Classification

Diagnosis and classification of CNS tumors are based on the 5 edition of the Central Nervous System Tumors volume of the WHO Classification of Tumors series https://publications.iarc.who.int/Book-And-Report-Series/Who-Classification-Of-Tumours/Central-Nervous-System-Tumours-2021, accessed on 21 May 2026), published in 2021. This framework integrates histology, immunohistochemistry, and molecular testing. The increasing impact of molecular diagnostics has led to significant changes in the classification, nomenclature, and grading of CNS tumors [12].
The nomenclature of these tumors takes into account multiple factors, including tumor cell origin, specific histological and molecular features, age, anatomical location, tumor grade, and molecular alterations. Traditionally, CNS tumor grading differed from that of other neoplasms, as it was applied across different tumor entities and correlated with an idealized clinical-biological behavior.
In the updated edition, the classification has shifted toward a within-type grading system.
This approach aligns more closely with grading systems used for non-CNS tumors, allowing greater flexibility in assigning grades relative to tumor type and better reflecting underlying biological behavior rather than clinical outcomes, e.g., overall survival, which are influenced by treatment. For example, there is neither grade 1 IDH mutant astrocytoma nor oligodendroglioma, nor grade 4 meningioma [13].

2.2. Immunohistochemical Markers

Immunohistochemistry (IHC) is a cornerstone of standard diagnostic pathology, acting as an indispensable bridge between histology and molecular biology. Beyond its established role in the diagnosis of CNS tumors, IHC also provides critical information for prognostic evaluation, survival prediction, and assessment of therapeutic response. By utilizing specific antibodies and biomarkers, IHC enables the characterization of tumor differentiation, maturation, and progression. Key IHC markers commonly used in the evaluation of CNS neoplasms are summarized in Table 1.
Table 1. Immunohistochemical markers in CNS tumors, according to the WHO 2021 framework [13].
Despite its central diagnostic role, IHC has important limitations in CNS tumor diagnostics, particularly in poorly differentiated or highly heterogeneous tumors. Interpretation of immunostaining is often influenced by staining intensity, distribution, fixation quality, and the absence of universally standardized positivity thresholds for several markers [14]. Moreover, many commonly used markers exhibit limited specificity and may show overlapping expression across distinct tumor entities. For example, Glial fibrillary acidic protein (GFAP), although considered a classical glial marker, may also be expressed in reactive astrocytes, ependymal tumors, schwannomas, and certain metastatic neoplasms, potentially complicating the distinction between reactive and neoplastic processes. Similarly, S-100 protein demonstrates broad expression across glial, Schwannian, melanocytic, and mesenchymal tumors, limiting its standalone diagnostic utility. Consequently, contemporary neuropathology increasingly relies on integrated diagnostic approaches combining histomorphology, immunophenotyping, molecular profiling, and methylome-based classification rather than on isolated marker interpretation.
GFAP is a cytoplasmic intermediate filament protein that is positive in most astrocytic tumors and is widely used to distinguish them from non-glial neoplasms [15]. However, GFAP expression is not limited to neoplastic astrocytes; it can also be observed in reactive and normal astrocytes, as well as in neoplastic and non-neoplastic oligodendrocytes and ependymal cells [16]. In gliosarcoma, the glial component is GFAP positive, whereas the sarcomatous component is rich in reticulin. Moreover, in ganglioglioma, the ganglionic component expresses neuronal markers. Notably, GFAP expression tends to decrease with increasing tumor grade, reflecting poorer differentiation of the tumor [15].
Additional immunohistochemical markers may provide diagnostic value in specific tumor subtypes. In diffuse gliomas, oligodendrocyte transcription factor 2 (Olig2) supports glial differentiation but is not specific for oligodendroglioma. By contrast, α-thalassemia/mental retardation syndrome X-linked (ATRX) loss is typically associated with astrocytic lineage, whereas retained ATRX expression is generally expected in oligodendroglioma in the appropriate molecular context. In ependymomas, typical markers include vimentin, S-100 protein, synaptophysin, focal cytokeratin (CK), and epithelial membrane antigen (EMA), often showing a characteristic perinuclear dot-like pattern. Myxopapillary ependymoma represents a distinct subtype with a peculiar histomorphology and a typical location, almost exclusively, in the filum terminale and conus medullaris. It is usually EMA-negative, while GFAP positivity helps to exclude other tumors that may typically arise in this region, such as chordoma, chondrosarcoma, or paraganglioma. Importantly, GFAP is not completely specific for glial cells, as it may be expressed in schwannomas, choroid plexus tumors, and certain tumors of salivary and sweat glands [17]. Diagnostic pitfalls may arise in tumors with atypical immunophenotypes. For instance, GBMs with reduced or absent GFAP expression may be misinterpreted as metastatic carcinoma or sarcoma, particularly in small biopsy samples. Conversely, focal cytokeratin or EMA expression in high-grade gliomas and ependymomas may mimic metastatic epithelial tumors. Similarly, loss of ATRX expression is highly supportive of astrocytic lineage; however, technical artifacts and subclonal loss patterns may complicate interpretation. These limitations underscore the importance of correlating immunohistochemical findings with morphology, radiological features, and molecular analyses.
Vimentin is another cytoplasmic intermediate filament protein, but it is highly non-specific. It is expressed in a wide range of mesenchymal origin, mesenchymal and epithelial tumors, developing neurons, and glial tumors. In astrocytomas, vimentin shows strong positivity, mostly in an inverse relationship with GFAP, with the highest expression in high-grade tumors. Also, it is expressed in ependymomas and meningiomas, while it is typically negative or weakly positive in oligodendrogliomas [18].
CKs are intermediate filaments present in almost all epithelial cells and comprise at least 20 subtypes based on their molecular weight. While they are present in normal epithelium and epithelial tumors, variable expressions may also occur in numerous mesenchymal and other tumors. In CNS, CK positivity is uncommon, found mainly in choroid plexus tumors and certain meningioma subtypes. Their principal diagnostic value in neuropathology lies in differentiating primary CNS tumors from metastatic lesions [19].
Synaptophysin is a major transmembrane glycoprotein expressed in normal, reactive, and neoplastic neuroectodermal or neuroendocrine cells, making it a preferred marker for tumors of neuronal or neuroendocrine origin. During early neurogenesis, other markers such as β-tubulin may be expressed instead. In neuroendocrine tumors, such as paraganglioma, chromogranin A is also typically positive [17,20].
S-100 protein is a calcium-binding protein, originally isolated from the CNS. It is expressed in glial cells, Schwann cells, and melanocytes, and tumors derived from these lineages. It is also found in many other cell types, including chondrocytes, adipocytes, and myoepithelial cells, as well as their neoplastic counterparts [17,21]. S-100 positivity is also seen in Langerhans cell histiocytosis and may be present in small percentages in meningiomas, usually focally and with low intensity [22].
EMA is a glycoprotein considered a marker of normal and neoplastic epithelium and perineurium. Although primarily associated with epithelial differentiation, EMA expression has also been reported in various mesenchymal tumors, melanomas, and lymphomas. Within the CNS, EMA serves as a valuable diagnostic marker in the evaluation of meningiomas, ependymomas, chordomas, and metastatic carcinomas. In particular, EMA negativity is important for distinguishing schwannomas from solitary fibrous tumors, formerly termed hemangiopericytomas, which represent key histopathological mimickers of meningiomas. Additional differential diagnostic considerations include hemangioblastoma, which is typically EMA-negative, and metastatic renal cell carcinoma (RCC), which is generally EMA-positive. Despite their differing EMA expression profiles, these tumors may exhibit overlapping morphological characteristics and commonly express both vimentin and carbonic anhydrase IX (CA IX). However, several other immunohistochemical markers help distinguish them: hemangioblastoma shows positivity for vascular markers and stromal cell expression of α-inhibin, whereas renal cell carcinoma is positive for CK, paired box gene 8 (PAX8), and cluster of differentiation 10 (CD10) [13,17].
Leukocyte common antigen (LCA) does not differentiate between normal lymphocytes and lymphomas; therefore, a comprehensive IHC panel is required to determine B-cell, T-cell, or other lineage. Most primary CNS lymphomas are of B-cell origin. LCA is expressed in all leukocytes except plasma cells. Caution is required in LCA-negative lymphomas, such as plasmablastic and lymphoblastic lymphomas, anaplastic large cell lymphomas, and Reed-Sternberg cells in classic Hodgkin’s lymphomas [17].
Human melanoma black 45 (HMB-45) is a specific marker that is diffusely positive in primary melanocytic tumors from leptomeningeal melanocytes, as well as metastatic melanoma, which is the most frequent melanoma type in the CNS. Another specific marker is Melan A., whereas S-100 expression is typically elevated [17].
The IHC panel for CNS germ cell tumors is similar to that used for germ cell tumors in other anatomical locations. It does not help distinguish primary CNS from metastatic origin. Markers include placental alkaline phosphatase (PLAP), α-fetoprotein (AFP), human chorionic gonadotropin (HCG), cluster of differentiation 30 or 117 (CD30, CD117), and others, allowing diagnosis of germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma [17].
Ki-67 is used to assess tumor proliferative activity. It correlates with the prognosis, patient survival, and tumor grade. It is expressed during all active phases of the cell cycle [23,24]. In contrast, phosphohistone H3 (PHH3) occurs exclusively during mitosis. Another method of assessment is counting mitotic figures on hematoxylin-eosin staining [25].
Finally, p53 is a protein encoded by the tumor suppressor gene TP53 and plays a critical role in maintaining genomic stability. Positive p53 expression has been associated with poorer clinical outcomes, including reduced survival and accelerated progression toward higher-grade lesions [26].
Although several IHC markers remain indispensable in routine neuropathology due to their accessibility, rapid turnaround time, and cost-effectiveness, increasing diagnostic complexity has accelerated the transition toward molecularly integrated classification systems. Markers such as IDH1 R132H, ATRX, and H3K27M retain major practical importance because they correlate strongly with biologically defined tumor entities and can serve as reliable surrogates for molecular alterations. In contrast, less specific lineage-associated markers, including S-100, vimentin, and neuron-specific enolase (NSE), are progressively losing their independent diagnostic value owing to considerable overlap in expression patterns across different tumor types. Furthermore, methylome profiling and next-generation sequencing increasingly outperform conventional IHC in diagnostically ambiguous tumors, particularly in pediatric and poorly differentiated CNS neoplasms, where morphology and immunophenotype alone may be insufficient for accurate classification. Biomarker utility should always be correlated with multi-omics profiling and computational diagnostic consensus to address spatial intratumoral heterogeneity.

3. Genetic Alterations of Brain Tumors

3.1. Integrated Molecular Diagnosis

While histopathological examination and IHC remain fundamental components of CNS tumor diagnostics, the 2021 WHO Classification introduced an integrated diagnostic approach that combines histological, immunohistochemical, and molecular findings. This shift reflects the growing recognition that tumors with similar histomorphological features may differ substantially in their molecular profile, biological behavior, prognosis, and therapeutic response. Consequently, specific molecular alterations are now considered defining diagnostic criteria for several CNS tumor entities and are increasingly used for prognostic stratification and treatment selection.
Brain tumors represent a group of neoplasms arising from uncontrolled cell proliferation within the brain or the CNS. Their pathogenesis is closely associated with genetic and epigenetic alterations that disrupt key regulatory mechanisms, including cell cycle control, proliferation, and DNA damage response. Such changes enable tumor cells to evade normal growth constraints and promote tumor development and progression [27].
Over the past few decades, advances in molecular biology have significantly improved our understanding of the genetic landscape of brain tumors. A significant proportion of these tumors harbor specific genetic mutations that determine their biological behavior, aggressiveness, and response to therapeutic interventions [28]. Consequently, in the 5th edition of the WHO Classification of CNS Tumors, molecular diagnostics play a crucial role in tumor classification, often superseding purely histological criteria. This approach has enabled the distinction between adult- and pediatric-type gliomas, the redefinition of tumor subclassification (e.g., ependymomas and medulloblastomas), and the identification of entities defined primarily by molecular features [13].
Several pediatric CNS tumor entities are now classified using DNA methylation profiling (“methylome-defined” tumors). DNA methylation profiling analyzes genome-wide epigenetic patterns and allows identification of biologically distinct tumor subgroups that may not be distinguishable by histology alone [29].
Key genetic alterations in CNS tumors are summarized in Table 2.
Table 2. Representative molecular alterations in selected CNS tumor entities according to the 2021 WHO classification [13].
GBMs were among the first tumor types in which an epigenetic biomarker was successfully implemented in clinical practice [30,31]. DNA methylation profiling is essential or highly informative for the accurate classification of selected CNS tumor entities, particularly when histology and conventional molecular testing are insufficient, e.g., diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters, diffuse pediatric type-high-grade glioma H3-wildtype and IDH-wildtype, posterior fossa ependymomas or medulloblastomas, non-WNT/non-SHH. In addition, loss of H3K27 trimethylation (H3K27me3), which can be detected bIHC, serves as a valuable diagnostic marker for distinguishing posterior fossa ependymomas from other ependymoma subtypes [32,33].
Among the most well-characterized genetic alterations are mutations in the IDH1 and IDH2 genes, which are particularly associated with certain types of gliomas and are often linked to better prognosis. Amplification and overexpression of the EGFR gene play a crucial role in promoting tumor cell proliferation and survival, especially in more aggressive tumor forms. Mutations in the tumor suppressor gene TP53 lead to impaired control of the cell cycle and reduced ability to initiate apoptosis in response to genomic damage. In addition to these genetic changes, epigenetic modifications such as methylation of the O-6-methylguanine DNA methyltransferase (MGMT) gene promoter are of great clinical importance, as they can influence the tumor’s sensitivity to alkylating chemotherapeutic agents [34]. Furthermore, the BRAF V600E mutation is frequently observed in pleomorphic xanthoastrocytoma, often accompanied by positive BRAF immunoreactivity and CDKN2A deletion. TERT promoter mutations also represent recurrent molecular alterations across several CNS tumor subtypes. In contrast, pilocytic astrocytoma is commonly characterized by the presence of a KIAA1549–BRAF fusion, typically in the absence of detectable BRAF V600E immunoreactivity. Importantly, the diagnostic and prognostic utility of these biomarkers should be interpreted within the broader framework of multi-omics profiling and integrated computational diagnostic approaches to account for spatial intratumoral heterogeneity [35].
Some newly recognized entities, based on molecular findings, include pediatric tumors such as diffuse astrocytoma, diffuse low-grade glioma, diffuse midline glioma, diffuse hemispheric glioma, and diffuse pediatric-type high-grade glioma. Molecular-driven subclassification is used for entities previously known as ependymomas or medulloblastomas [13].
Among the most clinically relevant molecular markers in CNS tumors are IDH1/2 mutations, 1p/19q codeletion, EGFR amplification, TP53 alterations, and MGMT promoter methylation, each contributing to tumor classification, prognostic evaluation, and therapeutic decision-making.

3.2. IDH1/2 Mutations

According to the WHO 2021 classification, IDH mutation status is a key molecular criterion for classifying diffuse gliomas. Specifically, astrocytomas are defined by the presence of IDH mutations in the absence of 1p/19q codeletion, whereas oligodendrogliomas are characterized by the coexistence of IDH mutations and 1p/19q codeletion.
DHs comprise three isoenzymes, IDH1, IDH2, and IDH3, which catalyze oxidative decarboxylation reactions within the Krebs cycle [36]. IDH1 and IDH2 are located on chromosomes 2 and 15, respectively, and encode NADP+-dependent homodimeric enzymes sharing approximately 70% sequence identity. In contrast, IDH3 is a structurally distinct, mitochondrial NAD+-dependent heterotetramer that catalyzes an irreversible step of the tricarboxylic acid (TCA) cycle. Importantly, the oncogenic neomorphic mutations relevant to glioma biology predominantly involve IDH1 and, less frequently, IDH2, rather than IDH3 [37]. In terms of subcellular localization, IDH1 is found in the cytoplasm and peroxisomes, while IDH2 and IDH3 are localized within mitochondria [38]. Functionally, IDH1 and IDH2 catalyze the reversible oxidative decarboxylation of isocitrate to 2-oxoglutarate (2OG) in a reaction dependent on oxidized nicotinamide adenine dinucleotide phosphate (NADP+), while simultaneously producing reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for maintaining cellular redox balance. In contrast, IDH3 catalyzes the nicotinamide adenine dinucleotide (NAD+)-dependent conversion of isocitrate to 2-oxoglutarate within the tricarboxylic acid (TCA) cycle, a reaction that is regarded as irreversible under physiological conditions [37]. Mutations in IDH1 and, less frequently, IDH2 were first identified in GBMs through exome-wide sequencing studies in 2008 [39]. These mutations are highly prevalent in lower-grade gliomas, occurring in approximately 80% of grade II and III astrocytomas and oligodendrogliomas, and are also present in previously termed “secondary” GBMs that develop from these tumors [40]. The most common mutations in IDH1 and IDH2 involve a single amino acid substitution, in which arginine is replaced, leading to a neomorphic enzymatic activity. As a result, the normal product α-ketoglutarate (α-KG) is converted into D-2-hydroxyglutarate (D-2HG), an oncometabolite implicated in tumor biology. D-2HG has also emerged as a promising biomarker for monitoring therapeutic response [41]. In IDH-mutant tumors, intracellular D-2HG concentrations may reach levels ranging from 1 to 30 mM [42]. Under physiological conditions, D-2HG levels are tightly regulated, partly through transport mechanisms such as the citrate transporter (CTP/CIC). However, its accumulation in mutant cells is thought to contribute to tumorigenesis, although the exact molecular mechanisms remain not fully elucidated [38].
Due to its structural similarity to α-ketoglutarate (α-KG), D-2HG competitively inhibits multiple α-KG-dependent dioxygenases, including ten-eleven translocation (TET) DNA demethylases and Jumonji-C domain-containing histone demethylases [43]. This inhibition results in widespread epigenetic dysregulation characterized by DNA and histone hypermethylation, impaired cellular differentiation, and establishment of the glioma CpG island methylator phenotype (G-CIMP). In addition, altered dioxygenase activity affects hypoxia signaling, chromatin organization, and metabolic adaptation, thereby contributing to gliomagenesis and tumor progression [44].
IDH1/2, ATRX, and 1p/19q co-deletion are important for the division of gliomas into three groups. IDH1 mutations are present in most astrocytomas, oligodendrogliomas, and previously termed “secondary GBM”, but absent in “primary” GBM and ependymomas. Immunohistochemical staining for IDH1 is commonly used as an initial screening approach for detecting IDH alterations; however, because immunonegativity does not exclude the presence of less common IDH variants, additional molecular analyses may be required. Beyond IDH status, ATRX mutations represent another important molecular feature and are typically associated with loss of ATRX protein expression in tumor cells. Diffuse gliomas are currently classified according to the combined assessment of IDH mutation status, ATRX expression, and 1p/19q codeletion. Tumors harboring IDH mutation and 1p/19q codeletion are classified as oligodendrogliomas, whereas IDH-mutant tumors lacking 1p/19q codeletion, frequently associated with ATRX loss, are classified as astrocytomas. In contrast, diffuse astrocytic tumors with IDH-wildtype status that exhibit specific molecular features, including EGFR amplification, TERT promoter mutations, or the combined gain of chromosome 7 and loss of chromosome 10, are classified as IDH-wildtype glioblastomas [13].

3.3. EGFR Amplification

The EGFR gene, located on chromosome 7, encodes a transmembrane glycoprotein belonging to the receptor tyrosine kinase (RTK) family [45]. EGFR acts as a pivotal modulator of diverse intracellular signaling networks that regulate essential cellular functions, including proliferation, motility, survival, and neoplastic transformation. In normal physiology, EGFR signaling is strictly growth-factor-dependent. However, oncogenic alterations, such as point mutations or aberrant expression of receptor isoforms, can induce constitutive, ligand-independent activation, thereby facilitating tumorigenic processes [36]. In brain tumors, one of the most extensively studied EGFR alterations is the EGFR transcript variant III (EGFRvIII) [46]. EGFRvIII arises from genomic rearrangements associated with EGFR gene amplification and represents a tumor-specific receptor variant. Notably, its expression is restricted to GBMs and other malignant cells, while being absent in normal tissues, highlighting its potential diagnostic and therapeutic relevance [47]. EGFR gene amplification (EGFR Amp) is observed in approximately two-thirds of GBM, with roughly half of these cases also harboring EGFRvIII or single-nucleotide variants. This amplification leads to overexpression of the EGFR protein, thereby driving tumor cell proliferation, angiogenesis, and invasion through activation of the rat sarcoma (RAS) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Moreover, EGFR Amp-associated genomic rearrangements increase the frequency of EGFRvIII expression, which can initiate downstream signaling independently of extracellular ligands, further contributing to tumorigenic progression [45]. Despite initial sensitivity to RTK inhibitors, tumors harboring EGFR Amp often develop therapeutic resistance, as evidenced by clinical observations [48]. Due to their high prevalence and biological relevance, EGFR mutations and amplifications are considered important prognostic biomarkers in GBM [49].

3.4. TP53 Mutations

TP53 is a pivotal tumor suppressor gene located on chromosome 17 that encodes the nuclear transcription factor p53 [28], frequently described as the “guardian of the genome”. p53 regulates cellular responses to diverse stressors, including DNA damage, oncogene activation, nutrient deprivation, and hypoxic conditions [50,51]. Beyond its canonical role in maintaining genomic integrity, p53 regulates metabolism, stemness, autophagy, invasion, metastasis, interactions with the tumor microenvironment (TME), and immune responses [52]. Emerging evidence further indicates that the functions of p53 extend well beyond its classical roles in cell-cycle regulation and apoptosis, highlighting its pleiotropic effects in tumor biology [53]. In CNS tumors, p53 participates in remodeling the TME by modulating inflammatory cytokines, immune signaling, angiogenesis, and metabolic adaptation. Mutant TP53 may promote immunosuppressive tumor states and enhance glioma progression through interactions with hypoxia-related and pro-inflammatory pathways [54]. In addition, p53 has emerged as an important regulator of epitranscriptomic processes, including N6-methyladenosine (m6A) RNA modification pathways, which influence mRNA stability, stemness, and therapeutic resistance in cancer cells [55,56]. Another rapidly developing area is the role of p53 in ferroptosis, an iron-dependent form of regulated cell death associated with lipid peroxidation. Depending on the cellular context, p53 may promote or suppress ferroptosis by regulating targets such as SLC7A11, thereby influencing tumor survival, oxidative stress responses, and sensitivity to therapy. These non-canonical functions further highlight the central role of TP53 alterations in CNS tumor progression and therapeutic resistance [57,58,59].
Most TP53 alterations are missense mutations. In addition to the loss of their normal tumor-suppressive function, these TP53 mutants often acquire novel oncogenic properties that contribute to the development of malignant traits in cancer cells [60]. TP53 point mutations are significantly more prevalent in secondary brain tumors, occurring in approximately 90% of cases, compared to 30% in primary tumors, and may be absent in some primary lesions [61]. One proposed mechanism of tumor promotion involves dysregulation of the mevalonate (MVA) pathway [62].

3.5. MGMT Promoter Methylation

The MGMT gene, located on chromosome 10 [36], encodes a DNA repair enzyme that reverses DNA alkylation by removing alkyl groups from guanine, thereby preventing DNA damage-induced apoptosis [48]. MGMT promoter methylation represents one of the most clinically srelevant predictive biomarkers in GBM, IDH-wildtype, as reduced MGMT expression limits repair of temozolomide-induced O6-methylguanine lesions and is generally associated with increased sensitivity to alkylating chemotherapeutic agents, particularly temozolomide (TMZ) [28].
MGMT promoter methylation is detected in approximately 40% of GBMs. Historical studies using the former primary/secondary GBM terminology reported higher methylation frequencies in tumors previously termed secondary GBMs than in primary ones, with frequencies of approximately 75% and 36%, respectively [36]. These findings should be interpreted in light of the current WHO CNS5 classification, in which GBM is restricted to IDH-wildtype tumors, whereas many lesions formerly referred to as secondary GBMs are now classified as astrocytoma, IDH-mutant, CNS WHO grade 4, when current diagnostic criteria are met.
In normal tissue, most CpG sites within the MGMT promoter region remain unmethylated. In tumor cells, cytosine residues at these CpG sites are often methylated, increasing the binding affinity of proteins such as methyl-CpG-binding protein 2 (MeCP2) and methyl-CpG-binding domain protein 2 (MBD2). These proteins modify chromatin structure, inhibit transcription factor binding, and effectively silence MGMT expression [63].
Paradoxically, reduced MGMT expression enhances treatment efficacy, as tumor cells become less capable of repairing chemotherapy-induced DNA damage. Consequently, patients with MGMT promoter methylation show improved response to TMZ, making its assessment a critical component of clinical decision-making [64,65].

4. Epigenetic Alterations of Brain Tumors

Epigenetic regulation refers to heritable and reversible changes in gene expression that occur without alterations in the underlying DNA sequence. These mechanisms include DNA methylation, histone modifications, chromatin remodeling, enhancer regulation, and non-coding RNAs. Epigenetic regulation involves multiple mechanisms beyond histone modifications, including DNA methylation, alterations in chromatin architecture, long non-coding RNAs (lncRNAs), enhancer activity, and microRNAs (miRNAs). These epigenetic modifications can be stably transmitted through successive cell divisions, thereby contributing to the maintenance of cellular identity and function. Furthermore, cell signaling pathways, together with extracellular stimuli, can dynamically influence the epigenome, which regulates diverse biological processes through enzymes that modify transcription factors, DNA, and histones, as well as through the actions of non-coding RNAs [66]. Patients suffering from cancer based on different epigenetic profiles may have different manifestations and survival outcomes despite the same grade and stage of the disease. Epigenetic heterogeneity occurs at the cellular level, and each cell in a tumor may exhibit distinct epigenetic patterns, whether in specific genes, the genome as a whole, or histones [67]. The interplay among multiple epigenetic mechanisms may collectively contribute to tumor initiation and progression [66]. Dysregulated epigenomes (Table 3), including histone modifications, disorganized chromatin structure, DNA methylation, and non-coding RNAs, have been observed in brain tumors in adults and children over the past two decades [68,69].
Table 3. Key epigenetic mechanisms in CNS tumors.

4.1. DNA Methylation

Modification or repression of transcription is mediated by an epigenetic mechanism, DNA methylation, in which methyltransferases add methyl groups to promoter regions or CpG repeat sequences. As a stable epigenetic modification maintained through DNA replication, DNA methylation plays a critical role in regulating cellular processes, including differentiation, proliferation, and tumor initiation and progression. However, its effects can be reversed by DNA demethylation. A common epigenetic feature of cancer is promoter hypermethylation, which may silence tumor suppressor genes, TEN-ELEV together with global hypomethylation, which may contribute to genomic instability and aberrant oncogene activation. [70]. Oncogene expression occurs through methylation near enhancer regions, and tumor suppressor genes are repressed through methylation of CpG-rich sequences located within promoter regions. Both mechanisms enhance tumor growth [71]. Methylation typically occurs in CpG-rich regions of DNA with histones that are both hypoacetylated and hypermethylated [70]. An instance of this is methylation involving mutated IDH1/2 and, in the case of ependymomas, the development of the CpG island methylator phenotype (CIMP) [68]. Accumulation of D-2-hydroxyglutarate (D2HG; a defective product of the Krebs cycle) leads to a metabolic change initiated by the mutant enzyme IDH, which is frequently found in both children and adults in gliomas [72]. The accumulation of D-2-hydroxyglutarate creates an environment in which multiple mutations can arise later [73]. D-2HG exerts its oncogenic effects by inhibiting the Ten-eleven translocation (TET) DNA demethylases and Jumonji-C domain-containing histone demethylases. This inhibition promotes widespread promoter hypermethylation, thereby highlighting the central role of IDH mutations in driving tumor transformation and epigenetic reprogramming. [72]. IDH1 mutations occur in diffuse gliomas in children, and H3K36 and H3K27 methylation are also involved in the progression from low-grade gliomas to previously termed “secondary” GBMs [74]. Stable methylation patterns in ependymal cells suggest that they serve to assign them to cell lineages rather than to tumor progression [75]. Tumor treatment strategies involve inactivating IDH or blocking D2HG. GBM (GBM xenografts) growth was slowed after treating mice with DNA methylation inhibitors that had an IDH mutation [76]. Clinical studies have shown favorable results, especially with lower-grade tumors [77]. Preclinical studies have also demonstrated the therapeutic potential of IDH mutation-targeted immunotherapy in glioma treatment, either in combination with radiotherapy or together with TMZ [73,78]. Furthermore, additional mechanisms have been proposed involving metabolic and apoptotic pathways altered in IDH-mutant cells, although these remain to be fully elucidated [73,79]. Among epigenetic biomarkers, DNA methylation of the MGMT gene has emerged as a clinically important predictor of treatment response in GBM. When the MGMT promoter is unmethylated, MGMT expression is generally maintained, enabling tumor cells to repair TMZ-induced O6-methylguanine lesions and thereby contributing to treatment resistance. Conversely, promoter methylation reduces MGMT expression and is associated with improved response to TMZ.
Methylated promoter regions are found in only 30% of patients who respond favorably to chemotherapy, e.g., TMZ, compared to patients who have unmethylated promoter regions [80]. Clinical treatment (phase I/II) via glycogen synthase kinase 3β inhibition together with TMZ enhanced the effect of TMZ without adverse side effects and increased survival in unmethylated MGMT-related promoter regions [81]. In another study, the increase in TMZ through inhibition of glycogen synthase kinase 3β was based on cytosine methylation in the promoter region of the MGMT gene [82].

4.2. Histone Modifications

The main histone modifications include demethylation/methylation and deacetylation/acetylation [71], as well as phosphorylation and ADP ribosylation [83], which can be activating/deactivating in relation to gene expression [71]. Less common histone modifications, e.g., in GBM, are lactylation, succinylation, and crotonylation [84]. Histone modifications primarily occur at the N-terminal tails or within the core domains of histone proteins. Histone methylation can either activate or repress gene expression depending on the specific amino acid residue involved and the degree of methylation, typically mediated by methyltransferases through the addition of one, two, or three methyl groups to lysine or arginine residues. Importantly, this process is reversible and can be regulated by histone demethylases [70]. The most well-known are histone modifications on lysine residues in the N-terminal ends of both H4 and H3 [85]. In cancer cells, a tight chromatin configuration is created by the loss of histone marks of tumor suppressor genes and by the relaxation of chromatin conformation after the loss of repetitive regions or suppressor marks in subtelomeric DNA [83]. In approximately 80% of patients with diffuse midline glioma and in 20% of pediatric patients with GBM, this epigenetic alteration is driven by an H3 K27M mutation, resulting from a a lysine-to-methionine substitution at residue 27 of histone H3 or H3.3. The mutant histone interferes with Polycomb repressive complex 2 (PRC2) activity, leading to widespread loss of H3K27me3 and extensive transcriptional reprogramming.
The H3K27M oncohistone inhibits PRC2 enzymatic activity, leading to a global reduction in H3K27 trimethylation and profound transcriptional reprogramming [86]. The H3K27M oncohistone inhibits PRC2 enzymatic activity, leading to a global reduction in H3K27 trimethylation and profound transcriptional reprogramming. Loss of H3K27 trimethylation (H3K27me3) can also occur in posterior fossa group A ependymomas through mechanisms that are frequently independent of H3K27M mutations [87]. This epigenetic alteration contributes to aberrant transcriptional regulation and may promote oncogene activation [86]. In addition, histone H3 lysine demethylases are also expressed in GBM [31]. Interestingly, diffuse midline glioma is dependent on PRC2 activity for growth despite the aforementioned 2 inhibition [88]. However, in medulloblastoma, PRC2-1 expression is increased [89]. The H3 variant is important in this, where H3K27M occurs with PI3K (phosphoinositide 3-kinase) and with ACVR1 (activin-receptor type 1) and H3.3.K27M, which is less differentiated, more aggressive, and occurs with TP53 deletions [90,91]. Preclinical and clinical investigations evaluating PRC2/enhancer of zeste homolog 2 (EZH2) inhibitors, such as tazemetostat, are currently underway for the treatment of medulloblastoma, GBM, and ependymoma [66].
On 6 August 2025, the U.S. Food and Drug Administration (FDA) granted accelerated approval to dordaviprone, an oral imipridone and protease activator, for adult and pediatric patients aged 1 year and older with diffuse midline glioma harboring an H3K27M mutantion and progressive disease following prior therapy. This approval was based on an integrated efficacy population of 50 patients enrolled across five open-label, non-randomized trials, with an overall response rate of 22% and a median duration of response of 10.3 months. Therefore, dordaviprone should be discussed as a recently approved targeted systemic option for a molecularly defined and recurrent/progressive disease setting, rather than as a broadly effective treatment for all histone-mutant CNS tumors [92]. Specifically, dordaviprone acts through a dual mechanism, since it is an allosteric activator of the mitochondrial caseinolytic protease P (ClpP) and a selective antagonist of the dopamine receptor D2, thereby triggering a stress response, promoting apoptosis and cell cycle arrest, or exerting antiproliferative effects [92]. Dordaviprone was approved for recurrent H3K27M-mutant diffuse midline glioma because these tumors have unique epigenetic and metabolic vulnerabilities. Although other tumors also carry histone mutations, they differ biologically and may not depend on the same pathways targeted by the drug, such as mitochondrial stress responses, ClpP activation, or DRD2 signaling [92,93,94]. Therefore, histone mutations alone do not predict sensitivity. Toxicity data from clinical studies showed mainly manageable adverse effects, including fatigue, nausea, headache, vomiting, lymphopenia, elevated liver enzymes, and QTc prolongation. Compared with conventional chemotherapy, dordaviprone appears relatively well tolerated, with limited severe hematologic or neurologic toxicity [92,95].
Treatment also takes place with poly ADP-ribose polymerase inhibitors, which participate in the repair of DNA breaks and chromatin remodeling through histone modifications. Olaparib combined with TMZ was favorably tolerated (phase I). Other histone modifications affecting gene expression are acetylation and bromodomain and extraterminal proteins, for which treatment consists of deacetylase inhibitors and inhibitors of the given proteins [66].

4.3. miRNA Regulation

Additional epigenetic regulators implicated in tumor biology include non-coding RNAs, particularly miRNAs and lncRNAs. Most miRNAs are transcribed from independent genomic loci and subsequently undergo a multistep maturation process involving the generation of precursor miRNAs before becoming functionally active [96]. These molecules regulate gene expression primarily through post-transcriptional modulation of mRNA translation and stability [97]. Depending on their biological context and target genes, miRNAs may function either as oncogenes or as tumor suppressors during tumor development and progression [66]. MiRNAs regulate DNA methylation through DNA methyltransferases (DNMTs) or methylation-related proteins [98]. Under non-pathological conditions, they participate in apoptosis, angiogenesis, cell cycle, and DNA repair [66]. In adult brain tumors, several tumor-suppressive miRNAs are downregulated as tumor suppressors. Examples in GBM include miR-124, miR-138, miR-7, miR-181a/b, miR-128, miR-137 [99,100]. The accumulation of methyl groups in the promoter region suppresses the expression of, e.g., miR-410 in GBM, which could prevent cell division [101]. Targeting DNMTs via miR-185 resulted in the reversal of DNA methylation and the methylation of hypermethylated genes in GBM. Similarly, miR-101 reduced histone methylation, targeting DNMT3A, Embryonic Ectoderm Development (EED), and EZH2 in GBM to reactivate repressed (hypomethylated) genes [102].
Conversely, selected miRNAs, such as miR-21 in GBM [103], may function as oncogenic miRNAs and contribute to invasion, proliferation, drug resistance, and cell survival [104]. In addition to miR-21, miR-155, and miR-34a are accompanied by hypomethylation [105]. Tumor suppressor miRNAs such as miR-125b, miR-218, and miR-1253 have been observed in pediatric patients with diffuse midline glioma and medulloblastoma [106]. Histone deacetylation is also associated with the suppression of miRNA genes [105]. Therapeutic strategies involving miRNAs primarily focus on either restoring the expression of tumor suppressor miRNAs or inhibiting oncogenic miRNAs. Various delivery approaches have been explored to optimize therapeutic efficacy. Locoregional administration can bypass the BBB, thereby enhancing target-site delivery, although this approach is inherently more invasive. Alternatively, systemic administration utilizes both viral and non-viral delivery systems. Viral vectors, including adenoviruses and retroviruses, offer efficient gene delivery, whereas non-viral platforms, typically based on polymers and lipid-derived carriers, are generally considered safer and exhibit improved biocompatibility [106]. Tumor suppressors are restored using miRNA mimetics (single- or double-stranded synthetic RNAs) that functionally mimic endogenous miRNAs, or an indirect method using a viral vector that subsequently expresses the miRNA. Oncogenic miRNAs are inhibited using a non-viral method using antagomirs or antisense oligonucleotides that bind to miRNAs and cause degradation of mature miRNAs [107].

6. Conclusions

CNS tumors remain among the most complex and challenging malignancies because of their marked heterogeneity, aggressive clinical behavior, and limited response to conventional therapies. The shift from purely histopathological classification to integrated molecular diagnostics, as reflected by the 2021 WHO Classification of CNS Tumors,, has substantially improved tumor definition and patient stratification. However, this framework does not fully capture the spatial, temporal, and cellular heterogeneity that characterizes tumors such as GBM, where single-sample diagnosis may underestimate clinically relevant subclones and evolving resistance mechanisms.
In this scenario, multi-omics integration, spatial and longitudinal profiling, liquid biopsy, and AI-based analytical tools may help refine diagnosis, identify actionable vulnerabilities, and support biomarker-driven therapeutic strategies. Nevertheless, these approaches should not be viewed as standalone solutions, as their clinical impact will depend on robust validation, standardization, and integration with histopathological and molecular data. Similarly, emerging therapeutic strategies, including targeted agents, multi-target compounds, theranostics, and protein degradation approaches, remain promising but face major translational barriers, particularly BBB/BTB penetration, tumor heterogeneity, and therapeutic window limitations.
Overall, four take-home messages emerge from this analysis:
  • CNS tumor diagnosis is progressively moving from morphology-centered classification (e.g., by WHO 2021) toward integrated approaches incorporating molecular and methylome profiling.
  • Tumor heterogeneity and cellular plasticity continue to represent major challenges that limit both diagnostic precision and therapeutic efficacy.
  • The evaluation of emerging therapeutic strategies should extend beyond target relevance and also consider critical parameters such as BBB/BTB permeability, brain exposure, safety profiles, and therapeutic-window limitations.
  • AI and multi-omics approaches offer powerful tools for tumor stratification and target discovery, but their clinical implementation requires standardization, external validation, prospective testing, and integration with expert neuropathological interpretation.
Future advances in neuro-oncology will therefore require a multidisciplinary and precision medicine-oriented strategy that combines integrated diagnostics, computational modeling, mechanistic validation, and rational therapeutic development. Only through this critical integration will it be possible to move beyond descriptive molecular classification and achieve clinically meaningful improvements in patient outcomes.

Author Contributions

Conceptualization, B.L., S.M., N.U., A.B., P.S., I.D., A.T., M.K. and T.K.-S.; writing—original draft preparation, B.L., S.M., N.U., A.B., P.S., I.D., A.T., M.K. and T.K.-S.; writing—review and editing, B.L., S.M., N.U., A.B., P.S., I.D., A.T., M.K. and T.K.-S.; supervision, T.K.-S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by VEGA (VEGA 1/0648/25), KEGA (016UPJŠ-4/2026), and APVV (APVV-25-0038). This publication is based upon work from COST Action CA22103—A comprehensive network against brain cancer (Net4Brain), supported by COST (European Cooperation in Science and Technology). I.D.A. acknowledges financial support under the National Recovery and Resilience Plan (NRRP) (Mission 4, Component 2, Investment 1.1, Call for tender No. 104, published on 2 February 2022 by the Italian Ministry of University and Research (MUR)), funded by the European Union—Next Generation EU (Project Title: Fluorescent and Gadolinium-based Probes for the Targeted Surgery and Neutron Capture Therapy of Glioblastoma; CUP I53D23004870006; Grant Assignment Decree No. 20223ZFB2H; adopted on 19 June 2023 by the Italian Ministry of University and Research (MUR)).

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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