Edgar G. Ordóñez Rubiano1,2,3, Matías Baldoncini4, Alba Lucía Cómbita5,6, César Payán-Gómez7, Diego F. Gómez-Amarillo8, Fernando Hakim8, Luisa Fernanda Figueredo9, Valeria Forlizzi10, Carlos Castillo Rangel11, Sabino Luzzi12, Alvaro Campero13, Rafael Parra-Medina3,14
  1. Department of Neurological Surgery, Fundación Universitaria de Ciencias de la Salud, Hospital de San José - Sociedad de Cirugía de Bogotá, Bogotá, Colombia,
  2. School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia,
  3. Research Institute, Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia,
  4. Department of Neurosurgery, San Fernando Hospital, San Fernando, Argentina,
  5. Departament of Microbiology, Universidad Nacional de Colombia, Bogotá, Colombia
  6. Translational Research Group in Oncology, Instituto Nacional de Cancerología, Bogotá, Colombia
  7. Academic direction, Universidad Nacional de Colombia - Sede de La Paz, La Paz, Colombia
  8. Department of Neurosurgery, Hospital Universitario Fundación Santa Fé de Bogotá, Bogotá, Colombia,
  9. Department of Psychiatry, New York University Langone Health, New York City, USA,
  10. 0Department of Anatomy, University of Buenos Aires, Buenos Aires, Argentina,
  11. 1Department of Neurosurgery, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico City, Mexico,
  12. 2Department of Neurosurgery, University of Pavia, Polo Didattico “Cesare Brusotti”, Pavia, Italy,
  13. 3Hospital Padilla de Tucuman, Tucuman, Argentina.
  14. 4Department of Pathology, Instituto Nacional de Cancerología Bogotá, Bogotá, Colombia.

Correspondence Address:
Edgar G. Ordóñez-Rubiano, Department of Neurological Surgery, Fundación Universitaria de Ciencias de la Salud, Hospital de San José - Sociedad de Cirugía de Bogotá, Colombia.


Copyright: © 2023 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Edgar G. Ordóñez Rubiano1,2,3, Matías Baldoncini4, Alba Lucía Cómbita5,6, César Payán-Gómez7, Diego F. Gómez-Amarillo8, Fernando Hakim8, Luisa Fernanda Figueredo9, Valeria Forlizzi10, Carlos Castillo Rangel11, Sabino Luzzi12, Alvaro Campero13, Rafael Parra-Medina3,14. Understanding the molecular profiling of diffuse gliomas classification: A brief overview. 30-Jun-2023;14:225

How to cite this URL: Edgar G. Ordóñez Rubiano1,2,3, Matías Baldoncini4, Alba Lucía Cómbita5,6, César Payán-Gómez7, Diego F. Gómez-Amarillo8, Fernando Hakim8, Luisa Fernanda Figueredo9, Valeria Forlizzi10, Carlos Castillo Rangel11, Sabino Luzzi12, Alvaro Campero13, Rafael Parra-Medina3,14. Understanding the molecular profiling of diffuse gliomas classification: A brief overview. 30-Jun-2023;14:225. Available from:

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Background: Gliomas represent almost 30% of all primary brain tumors and account for 80% of malignant primary ones. In the last two decades, significant progress has been made in understanding gliomas’ molecular origin and development. These advancements have demonstrated a remarkable improvement in classification systems based on mutational markers, which contribute paramount information in addition to traditional histology-based classification.

Methods: We performed a narrative review of the literature including each molecular marker described for adult diffuse gliomas used in the World Health Organization (WHO) central nervous system 5.

Results: The 2021 WHO classification of diffuse gliomas encompasses many molecular aspects considered in the latest proposed hallmarks of cancer. The outcome of patients with diffuse gliomas relies on their molecular behavior and consequently, to determine clinical outcomes for these patients, molecular profiling should be mandatory. At least, the following molecular markers are necessary for the current most accurate classification of these tumors: (1) isocitrate dehydrogenase (IDH) IDH-1 mutation, (2) 1p/19q codeletion, (3) cyclin-dependent kinase inhibitor 2A/B deletion, (4) telomerase reverse transcriptase promoter mutation, (5) α-thalassemia/ mental retardation syndrome X-linked loss, (6) epidermal growth factor receptor amplification, and (7) tumor protein P53 mutation. These molecular markers have allowed the differentiation of multiple variations of the same disease, including the differentiation of distinct molecular Grade 4 gliomas. This could imply different clinical outcomes and possibly impact targeted therapies in the years to come.

Conclusion: Physicians face different challenging scenarios according to the clinical features of patients with gliomas. In addition to the current advances in clinical decision-making, including radiological and surgical techniques, understanding the disease’s molecular pathogenesis is paramount to improving the benefits of its clinical treatments. This review aims to describe straightforwardly the most remarkable aspects of the molecular pathogenesis of diffuse gliomas.

Keywords: Classification, Diffuse glioma, Glioblastoma, Glioma, Molecular pathology


Gliomas represent about 30% of all primary brain tumors and are responsible for the majority of primary brain tumor deaths.[ 37 , 56 ] Diffuse gliomas are believed to originate from neuroglial stem cells and are classified histologically as astrocytomas, oligodendrogliomas, and glioblastomas (GBMs) based on morphologic similarities to neuroglial cell types found in normal tissue. They are classified according to the tumor’s location (e.g., midbrain or thalamus), or also according to their characteristic patterns of differentiation, and features of anaplasia. The absence or presence of anaplastic attributes is used to assign grades of malignancy from Grade I to IV according to the 2007 World Health Organization (WHO) classification of the central nervous system (CNS) (WHO CNS3).[ 28 - 30 ] To date, diffuse gliomas are still classified by location and by their histology. Even though, this is not enough in terms of survival and chemo/ radiosensitivity characterization. Several studies in the last decades have examined the molecular features of these tumors and have intended to correlate these findings with the clinical behavior and the prognosis of these patients. As a result, the last two consecutive 2016 (WHO CNS4)[ 29 ] and 2021 (WHO CNS5)[ 30 ] editions of the WHO classification have also included molecular profiling.

In different scenarios, health-care providers of different specialties are involved in the treatment of patients with gliomas and should be familiarized with terminology regarding patients’ tumor diagnoses. Neurooncologists and neurologists as well as neurosurgeons should understand not only the terminology of molecular profiling but also the biological meaning and the implications behind these terms. In this review, we aim to describe and summarize the most remarkable aspects of the molecular pathogenesis of adult diffuse gliomas.


The authors performed a narrative review of the literature including each molecular marker described for adult diffuse gliomas used in the WHO CNS5. A MEDLINE/PUBMED search was based on the references of retrieved literature. This review included a comprehensive overview of the 3rd, 4th, and 5th editions of the WHO classification.


Histopathological classification

According to the WHO CNS3, gliomas include astrocytomas of various grades (diffuse astrocytoma [Grades II and III] and GBM [Grade IV]), oligodendrogliomas (Grades II and III), and mixed oligoastrocytomas (Grades II and III) [ Table 1 ].[ 56 ] Despite worldwide use of this classification given the relatively easy way to determine cell predominance at the microscopic view, multiple concerns remained in terms of mixed cellular cases and lack of additional information to investigate for clinical prognosis. In the last decade, there has been meaningful progress in the comprehension of the molecular pathogenesis of gliomas. These advancements have improved diagnostic and classification systems.[ 28 - 30 ] Furthermore, a better understanding of the molecular pathogenesis of these tumors has identified new molecular targets and has outlined therapeutic strategies that could improve the results in the treatment of this pathology. However, at present, the classic prognostic factors, such as the patient’s age, general functional status, and neurological status, as well as the extent of resection, continue to determine the prognosis of these patients.[ 56 ] This highlights the importance of identifying other molecular markers that allow defining the prognosis of this pathology from diagnosis and identifying potential therapeutic targets that allow establishing new and more efficient therapeutic strategies.

Table 1:

2007 WHO classification of gliomas based on histopathology.


Molecular classification

The WHO Grade II–III gliomas are the most prevalent gliomas in young adults and are characterized by diffuse infiltration of the brain and their proclivity for recurring and malignant progression. Histological classification had previously distinguished astrocytic, oligodendroglial, and mixed oligoastrocytic tumors. However, molecular markers have now revealed evidence of only two subtypes: (1) the astrocytic genotype, which is characterized by mutations in tumor protein P53 (TP53), often accompanied by a mutation in the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, and (2) the oligodendroglial genotype, which is characterized by the codeletion of 1p and 19q chromosomal arms (1p/19q codeletion), associated with the mutation of the telomerase reverse transcriptase (TERT) promoter (TERTp).[ 21 , 47 ] Even though, the oligoastrocytic genotype was still included in the next version of the WHO classification, published in 2016,[ 29 ] where its differentiation remained highly controversial [ Table 2 ]. The WHO CNS4 still gave substantial importance to histological information, and this certainly influenced the presence of the oligoastrocytoma in this version.

Table 2:

2016 WHO classification of diffuse gliomas.


To improve the classification of diffuse gliomas, the WHO CNS5[ 30 ] eliminated oligoastrocytoma as a separate entity and converged in astrocytomas or oligodendrogliomas. This version summarized the most important features of molecular profiling of diffuse glioma, leading to better characterization. This edition included the loss of ATRX, mutation of the TP53, the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene deletion, the epidermal growth factor receptor (EGFR) amplification, and TERTp mutation [ Table 3 and Figure 1 ]. In addition, the nomenclature was changed from Roman numbers to Arabic numbers to refer to the histological grade. This classification has made it possible to differentiate new entities, differentiating mutant isocitrate dehydrogenase (IDH) Grade 4 astrocytoma from GBM, which necessarily have the IDH wildtype status. This has made it possible to partially clarify why some Grade 4 gliomas have a better prognosis than others and reclassify the previously called “secondary GBM.” Undoubtedly, in the near future, the complementary study with transcriptomics and proteomics will improve this classification, showing the variety of pathologies framed within the group of diffuse gliomas. Thus, in addition to the histopathological study, the complete molecular profile for the study of diffuse gliomas should include preferably the analysis of the presence or absence of (1) IDH-1 mutation, (2) 1p/19q codeletion, (3) loss of ATRX, (4) TP53 mutation, (5) CDKN2A/B deletion, (6) EGFR amplification, (7) TERTp mutation, as well as (8) gain of chromosome 7, and (9) loss of chromosome 10 [ Table 4 ]. Most of these genes encode receptor tyrosine kinases and their downstream signaling companions. Here, we will resume these mutational markers and their role in diffuse glioma pathogenesis.

Table 3:

2021 WHO classification of diffuse gliomas.


Figure 1:

The World Health Organization Central Nervous System 5. Molecular biomarkers used for classifying diffuse gliomas. A simple resume for easy differentiation of the presence of mutations in each entity is demonstrated. Sequential acquisition of markers can be performed to perform a correct diagnosis. The five different subtypes of diffuse gliomas are shown. DA: Diffuse astrocytoma, ODG: Oligodendroglioma, GBM: Glioblastoma, IDHmut: Isocitrate dehydrogenase mutated, ATRX: Alfa-thalassemia/mental retardation syndrome X-linked, CDKN2AB: Cyclin-dependent kinase inhibitor 2A/B, EGFR: Epidermal growth factor receptor, TERT: Telomerase reverse transcriptase.


Table 4:

Molecular profile of diffuse gliomas.


Hallmarks of cancer: Diffuse gliomas

As the global tendency is to characterize and classify tumors by their molecular behavior, it is of major importance to enhance the intrinsic properties of tumors described in the last decade. All gliomas, but more specifically GBM are recognized by their malignant behavior and their complex molecular biology. To understand these malignant properties, it is fundamental to comprehend the basis of cancer. Hanahan and Weinberg proposed the “Hallmarks of Cancer” as a set of functional capabilities that make cells their way from normalcy to neoplastic growth states, which are characteristics that are basic for their ability to form cancer.[ 17 ] Six hallmarks were initially proposed, including (1) the acquired capabilities for sustaining proliferative signaling, (2) evading growth suppressors, (3) resisting cell death, (4) enabling replicative immortality, (5) inducing/accessing vasculature, and (6) activating invasion and metastasis. Afterward, in 2011, two additional enabling characteristics were added: (1) genome instability and mutation and (2) tumor-promoting inflammation. Furthermore, two additional “emerging hallmarks” were included: (1) deregulating cellular energetics and (2) avoiding immune destruction.[ 18 ] In the updated 2022 version of the proposed hallmarks of cancer, a total of 14 hallmarks were included in the study [ Figure 2 ].[ 16 ] In the 2022 version, the 2011 “emerging hallmarks” and the enabling characteristics were included in the core hallmarks. In addition to these 10, the following emerging hallmarks were also incorporated: (1) unlocking phenotypic plasticity and (2) nonmutational epigenetic reprogramming, and two enabling characteristics were included as well: (1) polymorphic microbiomes, and (2) senescent cells. Recently, Belotti et al. described prognostic neurotransmitter receptor genes that may be associated with cancer hallmarks in gliomas. These genes were differently associated when comparing low-grade gliomas (LGG) and GBM, particularly with immune response.[ 6 ] Despite several studies that have explored these hallmarks separately, further studies are needed to explore these hallmarks as wholesome in gliomas.

Figure 2:

Core mutational hallmarks of cancer.


Core mutational markers

Core mutational markers have been described for diffuse gliomas given the importance of differentiating separate entities in terms of biological behavior and the influence on clinical prognosis. These markers have been identified in multiple studies demonstrating the presence or not in each different glioma subtype. Hereafter, we resume the most valuable information regarding these core molecular markers.

IDH-1 mutation

Diffuse gliomas of both genotypes can carry mutations in the gene for the enzyme IDH 1 (IDH1) [ Figure 3 ] or, less frequently, in IDH2.[ 4 , 59 ] IDH1 and IDH2 are very similar genes and will be used collectively as IDH hereafter. The IDH mutation likely represents the tumor-initiating alteration in most diffuse gliomas, except for the rare tumors arising in patients with a germline TP53 mutation who secondarily acquire IDH mutations.

Figure 3:

Impairment of cellular metabolism in IDH mutant diffuse gliomas. The enzyme isocitrate dehydrogenase 1 normally catalyzes the oxidative decarboxylation of isocitrate to form 2-oxoglutarate (α-KG). When the enzyme is mutated, it shows a gain in function to produce D-2-hydroxyglutarate from α-KG. α-KG: Alpha-ketoglutarate, IDH1: Isocitrate dehydrogenase 1, IDH1mut: Mutated isocitrate dehydrogenase 1, D-2HG: D-2 hydroxyglutarate. (Created with, NADPH: Reduced nicotinamide adenine dinucleotide phosphate, NADP+: Oxidized nicotinamide adenine dinucleotide phosphate.


IDH enzymes normally catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (alpha-ketoglutarate [α-KG]), thus generating nicotinamide adenine dinucleotide phosphate (NADPH) from NADP+. When the gene is mutated, the enzyme shows a gain in function to produce D-2-hydroxyglutarate (D-2HG) from α-KG, demonstrating a decreased NADPH production, which probably predisposes cells to oxidative stress.[ 44 ] Elevated levels of D-2HG in IDHmut cells have been shown to competitively inhibit the activity of α-KG-dependent dioxygenases, including demethylated histones and the 5-methylcytosine hydroxylases of the “ten-eleven translocation” (TET) enzymes. D-2HG is an oncometabolite that has been associated with profound effects on cellular epigenetic programs, differentiation patterns, and metabolic profiles.[ 40 ] This inhibition conducts to increased histone methylation and hypermethylation of multiple CpG islands in deoxyribonucleic acid (DNA), which is a characteristic epigenetic marker of IDHmut gliomas that has been termed as the glioma CpG island methylator phenotype.[ 52 ] However, the IDH mutation alone is not enough to cause the development of glioma.[ 48 ] IDHmut neuroglial progenitor or stem cells likely need to acquire additional genetic alterations to transform into astrocytomas (ATRX and TP53 mutations) or oligodendrogliomas (1p/19q codeletion and TERTp mutations).

1p/19q codeletion

Reifenberger et al. were the first in demonstrating that oligodendroglial tumors show allelic deletions on 19q (deletions in different regions of the short arm of chromosome 19 with similar phenotype) and the majority of tumors with 19q loss also show loss of alleles on lp.[ 42 ] Afterward, it was demonstrated that combined 1p/19q loss was associated with chemosensitivity and prolonged survival in anaplastic oligodendrogliomas.[ 10 ] 1p/19q loss is mediated by an unbalanced translocation with whole-arm deletions as a consequence of the loss of the derivative chromosome (1;19) (p10;q10), while the reciprocal derivative (1;19) (q10; p10) chromosome is retained [ Figure 4 ].[ 14 , 20 ] This is primordial because it explains why the combined loss of 1p and 19q is of increased significance than the loss of each chromosome arm individually.[ 39 ] The main reasons why 1p/19q codeletion is correlated with better outcomes remain unclear, but it is probably associated with a process that allows functioning apoptotic pathways to persevere or the loss of gene products that handle treatment resistance or grant tumor suppression.[ 39 ]

Figure 4:

Codeletion of 1p/19q. It is believed that an unbalanced whole-arm translocation between chromosomes 1 and 19 creates two derivatives chromosomes: der (1;19) (q10;p10) and der (1;19) (p10;q10). This translocation generates the loss of derivative chromosome der (1;19) (p10;q10), which contains 1p and 19q. (Created with


Loss of ATRX

The role of the ATRX gene in cancer has emerged in the past decade. The status of the ATRX is now pivotal for glioma classification and has been included as part of the molecular profile for glioma characterization.[ 30 ] The ATRX protein is part of the chromatin remodeling proteins and helps to maintain genomic stability through its deposition of the replication-independent histone variant H3.3 at telomeres.[ 38 ] Mutations on ATRX have been associated with the Alternative Lengthening of Telomeres (ALT) mechanism.[ 23 ] The loss of ATRX in gliomas promotes ALT and has been strongly associated with DNA damage and replicative stress.[ 9 ] Mechanisms of ATRX loss include deletions, mutations, or gene fusions, which may impact ALT and correlate with TP53 mutation.[ 36 ] The concurrence of IDH1, TP53, and ATRX mutations are characteristic of the IDHmut astrocytomas,[ 30 ] otherwise, the concurrence of 1p/19q codeletion and ATRX loss is extremely rare. ATRX mutations have been shown to correlate with worse progression-free survival and overall survival (OS) in IDHmut astrocytomas in comparison with oligodendrogliomas. However, ATRX mutations demonstrated better progression-free survival and OS when looking only within the group of IDHmut astrocytomas.[ 24 , 57 ]

TP53 mutation

TP53 is a tumor suppressor. Normal TP53 protein functions as an inhibitor of cellular replication when sustained DNA damage and its gene mutation leads to an impaired protein that alters its ability to bind DNA and prevent cell replication.[ 41 ] In gliomas, the mutation in TP53 is one of the most commonly detected alterations and acts as a remarkable molecular biomarker for therapeutic approaches.[ 15 ] In GBM, TP53 pathway dysregulation has been related to different cellular processes including evasion of apoptosis, migration, and proliferation, as well as invasion, among different processes.[ 54 , 58 ] The Cancer Genome Atlas (TCGA) ( demonstrated that TP53 mutation was present in 49% of all patients with LGG,[ 15 ] while it was shown to be the most frequently mutated gene in GBM.[ 11 ] Gliomas with a single mutation that codes for the R273C amino acid change have been found to have an increased progression rate and lower OS.[ 32 ]

CDKN2A/B homozygous deletion

According to the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy — Not Official WHO (cIMPACT-NOW) recommendation,[ 27 ] the WHO CNS5 adopted the CDKN2A/B homozygous deletion into the molecular characterization of diffuse gliomas. The prior consideration of malignant progression to secondary GBM was primarily confined to tumors with an astrocytic genotype. This malignant progression involves the homozygous deletion of the CDKN2A/B locus. As mentioned before this entity is now classified as “Astrocytoma, IDH mutant, Grade 4.”[ 30 ] The impact of this mutation relies on the poor prognosis and limited OS in IDHmut astrocytoma, regardless of histological tumor grade (OS ~3y).[ 2 , 43 , 51 ]

CDKs are core regulatory molecules that determine cellular progression through the cell cycle. Extracellular signals lead to complex formation between D-type cyclins and cyclin-dependent kinases 4 and 6 (CDK4/CDK6) [ Figure 5 ]. The generation of this complex promotes retinoblastoma protein (pRB) phosphorylation, as well as the release of elongation factor, and activation of genes related to the transition from the G1 to S phase.[ 43 ] CDKN2A is a gene located at chromosome 9 (band p21.3) and codes for the tumor suppressor proteins p16INK4a (aka INK4a) and p14 (aka alternate reading frame), which regulate the activities of p53 and the pRB in tumor suppression. p14 triggers cell-cycle arrest or apoptosis by inactivating the mouse double minute 2, which is an E3 ubiquitin-protein ligase targeting p53 for destabilization. This process generates p21 activation, which inhibits the activity of the cyclin/CDK complex, especially CDK2. In addition, p16INK4a promotes pRB-mediated cell-cycle checkpoints by inhibiting CDK4 that phosphorylates and inactivates pRB.[ 31 ] On the other hand, the CDKN2B gene, which is adjacent to CDKN2A, encodes the p15 protein (aka INK4B). This protein binds to CDK4/CDK6 and inactivates them, controlling cell proliferation.[ 19 ] The inclusion of the CDKN2A/B deletion into the WHO CNS5 elevates its status to that considered to microvascular proliferation and necrosis.

Figure 5:

Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion. In nonmutated cells, the CDKN2A gene synthesizes p16 and p14. p16 binds to and inactivates CDK4/6. The CDKN2B gene is adjacent to CDKN2A and encodes p15, which inactivates CDK4/6. The p14 protein is an alternate reading frame protein and prevents p53 degradation by inhibiting MDM2 activity. This generates the activation of p21, which binds to and inhibits the activity of CDK2. By binding to these cyclin-dependent kinases, p14, p15, and p16 block cell cycle progression from G1 to the S phase. On the other hand, when CDKN2A/B is homozygously deleted, the cells are unable to synthesize these tumor suppressor proteins. Consequently, there is an unrestricted generation of complexes between cyclins and cyclin-dependent kinases, which leads to increased Rb phosphorylation, a release of elongation factor, and uncontrolled activation of the genes involved in the progression from G1 to the S phase. (Created with, CDK4/6: Cyclin-dependent kinases 4 and 6, MDM2: Mouse double minute 2 homologous, RB: retinoblastoma protein, CDK2: Cyclin-dependent kinase 2.


EGFR amplification

EGFR is a cell transmembrane tyrosine kinase receptor, and its gene (EGFR) is in the chromosome band 7p12.1.[ 46 ] EGFR can be modified in several ways in diffuse gliomas especially in GBM by overexpression, amplification, and deletion mutants, among others.[ 46 ] Amplifications are a type of mutation that results in various copies of genes in chromosomal regions that induce the overexpression of proteins in neoplastic cells.[ 26 ] EGFR is one of the most amplified genes in cancer.[ 1 ] Particularly, in GBM, the EGFR gene amplification is associated with EGFR overexpression,[ 8 ] that leads to the activation of intracellular signaling pathways that promote cell proliferation and increased cell survival by blocking apoptosis. Some of the most remarkable activated pathways include RAS/RAF/MEK/MAPK and PI3K/Akt.[ 33 ] Amplified DNA can be presented in different forms, including as extrachromosomal elements called double minute chromosomes, which is the most frequent EGFR amplification pattern in GBM.[ 26 ] Some studies have suggested that EGFR amplification promotes invasion, proliferation, and resistance to radio/chemotherapy.[ 12 , 35 , 46 ] In terms of survival, literature is controversial. EGFR gene amplifications seem to change according to co-occurrence with other mutations including EGFRvIII deletion[ 50 ] or homozygous CDKN2A deletion.[ 7 ]

TERT promoter mutation

Telomerase is a protein mainly conformed by human telomerase ribonucleic acid and TERT. The telomerase is located within the cell nucleus, and its function is to synthesize a repetitive nucleotide sequence (TTAGGG) while creating the telomeres at the end of chromosomes to protect genomic DNA.[ 34 ] TERT is the catalytic subunit of the human telomerase, which is responsible for catalyzing the addition of the nucleotides in the TTAGGG sequence.[ 49 ] TERTp mutation derives in increased telomerase activity and lengthen telomeres.[ 13 ] Reactivation of TERT occurs due to mutations in hotspots located at −124 bp and −146 bp upstream of the TERT translation start site. There is an activation of somatic point mutations that substitute a cytosine for a thymidine (C > T) at position 228 (C228T) and/or 250 (C250T) of the TERTp. These mutually exclusive mutations are typically heterozygous and create 11 base pair sequences (“CCCGGAAGGGG”), a de novo E26 transformation-specific family transcription factor binding motif.[ 5 ]

Killela et al. reported that TERTp mutations were present in about 80% of GBM and oligodendrogliomas.[ 22 ] This suggests that TERTp mutation could even be more important in the cascade of mutation for gliomagenesis in comparison to other molecular markers. TERTp mutations represent a major mechanism of telomerase upregulation in gliomas and are critical for characterizing and classifying GBM. This poses a paramount role of telomerase and telomere elongation in the pathogenesis of gliomas.[ 3 ] Significance of TERTp mutation differs depending on the IDH status and the presence or not of 1p19q codeletion. When there is a triple-positive LGG (positive for TERTp mutation, IDH mutation, and 1p19q codeletion), the TERTp mutation represents a better prognosis, while when its present isolated in IDH-wildtype tumors, patients have the worse overall prognosis, even worse than triple-negative gliomas.[ 13 ]

Gain of chromosome 7 and loss of chromosome 10

Gain of chromosome 7 alone has shown an increased recurrence of gliomas in the pediatric population.[ 45 ] Particularly when sequencing GBM, a common pattern of concurrence of gain of chromosome 7 and loss of chromosome 10 has been described as a hallmark in this entity. In fact, this alteration has been identified in 100% of the classical subtype of GBM.[ 53 ] Lopez-Gines et al. found that lower survival rates in GBM were associated with the monosomy of chromosome 10, trisomy of chromosome 7, and the concurrence of both alterations.[ 25 ] Chromosome 7 gain and loss of chromosome 10, as well as EGFR amplification and TERTp amplification, are now used as hallmarks for GBM classification, distinguishing GBM from other diffuse glioma subtypes.[ 30 ] If needed, complementary analysis of chromosomal abnormalities should be added and addressed in GBM cases, particularly for chromosomes 7 and 10.


Glioma precision medicine

Just before the publication of the WHO CNS5, Weller et al. published the EANO guidelines of adulthood diffuse gliomas.[ 55 ] Despite these guidelines were based on the WHO CNS4, the in terms of integrated histomolecular classification the following recommendations remain the most updated for diffuse glioma: [ 55 ] (1) glioma classification should follow the most recent WHO CNS, complemented by cIMPACT-NOW updates, (2) IDH immunohistochemistry (R132H protein) and nuclear expression of ATRX should be performed routinely, (3) if IDH1 is negative then IDH 1 (codon 132) and IDH2 (codon 172) should be performed, (4) 1p/19q codeletion status should be determined in all IDH-mutant gliomas, (5) Methyltransferase promoter methylation status should be determined in GBM to guide in decision-making for the use of temozolomide, (6) CDKN2A/B homozygous deletions should be performed in IDHmut astrocytomas (this should be prioritized after WHO CNS 5), and (7) Chromosome +7/–10 signature, EGFR amplification, and TERTp mutation should be tested in IDHwt gliomas lacking microvascular proliferation and necrosis as histological features of the WHO Grade 4 to allow for a diagnosis of GBM.

In addition to separate all entities, the WHO CNS 5 allows to evaluate prognosis in terms of OS and chemo and radiosensitivity.[ 30 ] In the near future, many aspects including radiological assessment should be performed to differentiate these subtypes. Different approaches including radiological follow-up as well as evaluation of the connectome will guide adjuvant treatment and, if necessary, reoperations when indicated. Figure 6 demonstrates the radiological evaluation of an oligodendroglioma Grade 2 (1p/19q codeleted) in comparison with an IDHmut astrocytoma, Grade 4. Advanced neuroimaging, in relation to molecular classification, would elucidate how the tumor impact on neural organization and will help to understand the biology of the different glioma subtypes.

Figure 6:

Neuroimaging of an oligodendroglioma Grade 2 and of an isocitrate dehydrogenase (IDH) IDHmut astrocytoma, Grade 4. Case 1. Oligodendroglioma Grade 2. (a) Preoperative axial T1 postcontrast imaging demonstrating a nonenhancing perirolandic hypointense tumor. (b) Immediate postoperative enhanced magnetic resonance imaging (MRI) demonstrating near total resection of the tumor. (c) Preoperative connectivity map. White fibers are arranged in a symmetric distribution in both, left and right cortical tracts, noting in blue an increased signal diffusion in the right Aslant tract. Green arrowhead: Right corticospinal tract, Orange Arrowhead: Left corticospinal tract. Case 2. IDHmut astrocytoma, grade 4. (d) Preoperative enhanced MRI demonstrates a large enhancing perirolandic tumor consistent with a high-grade glioma. (e) 3-month follow-up MRI demonstrates adequate control with no enhancing tumor. (f) Preoperative connectivity map. White fibers are arranged in a symmetric distribution in both, the left and right cortical tracts, note in blue an increased signal diffusion in the right Aslant tract, the left corticospinal tract, and the right external capsule. Green arrowhead: Right corticospinal tract, Orange Arrowhead: Left corticospinal tract.



Here, we resume some of the most important current markers used for the molecular classification of diffuse gliomas. The understanding of the genetic origin of the molecular features of gliomas is mandatory for neurosurgeons and neuro-oncologists. The literature regarding this topic is overwhelming and increases day by day. The complex molecular structure among the various type of gliomas generates the investigation of targets for treatment one of the most challenging tasks for neuroscientists in this era. The most remarkable molecular markers must be included in the study for the diagnosis of these tumors whenever possible to guide in a case-by-case manner the adjuvant treatment. Certainly, differentiating all genetic/molecular subtypes of diffuse gliomas will demonstrate why the prognosis changes are sometimes notable between one case and another, even for tumors in the same molecular group with the same extent of resection rates. Finally, complementary genomic and transcriptomic studies must continue to be performed, as they will help to elucidate the covered origins of molecular cascades and will guide us to a better understanding of these neoplasms.

Declaration of patient consent

Patients’ consent not required as patients’ identities were not disclosed or compromised.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.


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