3.1. ATRX
The ATRX transcriptional regulator, also known as ATP-dependent ATRX helicase, X-linked helicase II, or X-linked nuclear protein (XNP), is encoded by the
ATRX gene in humans [
10].
ATRX is located on chromosome Xq21.1 and encodes a 280 kDa nucleoprotein that is involved in many cellular functions, including DNA recombination and repair and chromatin remodeling [
11]. ATRX undergoes cell cycle-dependent phosphorylation, which regulates its nuclear matrix and involvement in regulatory mechanisms in the cell [
12].
Hereditary mutations of
ATRX have been described in association with XLMR syndrome (X-linked mental retardation syndrome) and alpha-thalassemia. Acquired mutations have been reported in various types of human cancer, such as pancreatic neuroendocrine tumors, gliomas, astrocytomas, and malignant pheochromocytomas [
13]. In many studies,
ATRX gene alterations have been shown to be associated with prognosis and mostly correlate with favorable results [
14].
Studies by Pekmezci et al. [
14] and Han et al. [
15] suggest that specific characteristics of
ATRX loss of expression are linked to the response to temozolomide treatment. Glioblastoma patients lacking
ATRX expression appear to benefit more from this treatment [
15].
Mutations in the
IDH,
ATRX, and
TERT promoter and the correlations between them were analyzed in a study conducted by Ohba et al. [
16]. Immortalized cells overcome the telomere-related crisis by activating telomerase or the ALT process (alternative lengthening of telomeres) [
17]. In gliomas, telomerase is activated mainly by a mutation in the
TERT promoter, while ALT activation is usually associated with an
ATRX mutation. Although the mechanism used by the
ATRX mutation to induce ALT remains unclear, the loss of
ATRX alone is considered insufficient to induce ALT [
16,
17].
Tumor cell lines using ALT to maintain the length of the telomere usually show complex karyotype rearrangements consistent with genome instability that can occur with dysfunctional telomeres. The absence of the ATRX chromatin remodeling factor is the dominant prognostic marker in these types of cancer [
17].
A study by Liu et al. [
18] examined the association between
TERT and
ATRX mutations. Their findings provide a theoretical basis for further research and may improve the clinical diagnosis and treatment of gliomas in the future. They showed that mutations in the
TERT promoter are negatively associated with
ATRX expression in GBM. They also studied the effects of
IDH and
TERT mutations, Ki-67 protein expression, and age on
ATRX status. Sex, WHO grade, and Ki-67 expression did not appear to significantly affect
ATRX. However, age and
IDH mutations were found to be statistically related. The probability of
ATRX mutation increased by 8.8% for each additional year of age. Moreover, the probability of
ATRX mutation in
IDH-mutant GBM samples was 14 times higher than in
IDH-wild-type samples [
19]. They furthermore confirmed that
TERT promoter mutations are positively associated with age and WHO grade, but they worsen the overall prognosis in association with the
ATRX mutation present [
18,
19].
Bobeff et al. [
20] determined the levels of amino acids in the plasma of 18 patients diagnosed with GBM and in a control group of 15 healthy volunteers by liquid chromatography and LC-QTOF-MS spectroscopy. Phenylalanine and leucine levels were shown to be lower in patients with GBM if
ATRX gene expression was lost. They thus showed that the levels of free amino acids in the plasma of patients with GBM differ significantly from the levels in healthy people, so they can be used as a prognostic marker [
20].
Gulten et al. [
21] also addressed the loss of
ATRX expression. They performed a retrospective analysis of 83 patients with GBM to determine
ATRX and
IDH1 mutations and p53 expression. Of the entire group,
IDH1 mutation was detected in 9.6% of patients,
ATRX loss in 4.8%, and p53 expression in 12.05% [
21]. It was found that
IDH1 mutation, loss of
ATRX, and
p53 expression alone did not have a major impact on patient prognosis, but radiotherapy and chemotherapy have a positive effect on the survival of patients with these mutations [
21].
Several studies have identified positive correlations between patient survival and the presence of specific genetic alterations in glioblastoma. These alterations include mutations in the
IDH1 gene, expression of the
TP53 protein, and loss of expression of the
ATRX gene [
22,
23,
24].
Chaurasia et al. [
22] further categorized glioblastoma patients into three prognostic subgroups based on these markers: group 1: lacking both
IDH1 mutation and
TP53 expression; group 2: possessing
IDH1 mutation and
ATRX loss; group 3: having IDH1 mutation but lacking TP53 expression. Their findings suggest that patients in groups 2 and 3, characterized by specific combinations of these markers, exhibit improved survival outcomes [
22].
Separate research by Cai et al. [
23] investigated the expression of mutated
ATRX and
IDH1 alongside heat shock proteins (hsp27 and P-hsp27) in a large sample of GBM patients. While they observed elevated levels of hsp27 and P-hsp27 in aggressive types of glioblastoma, these proteins did not significantly impact patient survival [
16]. This finding led to the classification of glioblastoma into three distinct groups: group A: GBM with both
IDH1 mutation and
ATRX loss, group B: GBM expressing P-hsp27, and group C: all remaining samples.
Analysis of survival data revealed the longest average survival (19.6 months) in group A, followed by group B (15 months) and group C (13 months). These results support the notion that GBMs harboring both
IDH1 mutation and
ATRX loss exhibit a more favorable prognosis. Interestingly, the presence of P-hsp27 within group A (
IDH1 mutation and
ATRX loss) further improved patient outcomes [
25].
ATRX is involved in the replication and repair of damaged DNA. The CRISPR/Cas9-mediated genetic activation of
ATRX inhibits cell proliferation and angiogenesis, and genetic activation of
ATRX may serve as a prognostic marker in predicting sensitivity to temozolomide [
14,
15].
3.2. BRAF
BRAF is a human gene located on the long arm of chromosome 7 (7q34), encoding a serine-threonine protein kinase called B-Raf [
26]. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion.
Increased BRAF kinase activity causes the sustained activation of the MAPK signaling pathway with consequent increased rates of proliferation and long-term survival of tumor cells. The basis of successfully targeted treatment is, therefore, the inhibition of BRAF kinase to slow or stop the growth of tumor cells. This is possible thanks to BRAF inhibitors, including the protein kinase inhibitor vemurafenib (Zelboraf), which is used in the treatment of malignant melanoma [
27]. Research by Kleinschmidt-DeMasters et al. [
28] indicates the potential effectiveness of vemurafenib in treating
BRAF-mutant GBM [
28].
BRAF gene mutations can cause birth defects in cardiofaciocutaneous syndrome, which is characterized by heart defects, mental retardation, and facial changes. Acquired
BRAF mutations have been found in non-Hodgkin’s lymphoma, colorectal cancer, malignant melanoma, and brain tumors, including glioblastoma [
29].
Several studies have investigated the link between
BRAF mutations and prognosis in glioblastoma patients, particularly in younger ones [
30,
31,
32]. Zheng et al. [
30] found a higher prevalence of BRAF mutations in young women with glioblastoma. Their study included 16 patients aged 7–61, with all 16 exhibiting
BRAF mutations. Notably, younger patients in this study also showed a better prognosis [
30].
This age-dependent effect was further supported by Vuong et al. [
31]. Their research demonstrated a more favorable prognosis for children and young adults (under 35 years old) with GBM and proven
BRAF mutation. However, the presence of a BRAF mutation did not significantly impact prognosis in older patients [
31].
Takahaschi et al. [
9] also showed that
BRAF mutations are less common in adult patients with GBM. In their study,
BRAF mutation occurred in only one case, and this patient survived for 4 years after surgery [
9]. Similar results were obtained by Chi et al. [
32], where the survival of patients with proven
BRAF mutation was 16–36 months [
32].
In a study by Da et al. [
33], the activation of the RAS/RAF signaling pathway was found to play a critical role in the pathophysiology of GBM. They reported that it does not matter whether
BRAF mutation (m-
BRAF) or
BRAF amplification (a-
BRAF) is considered: both activate the RAS/RAF pathway but have different effects on the survival rate of patients with GBM. The a-
BRAF group had poorer survival than did the m-
BRAF group [
33].
These findings suggest a potential association between
BRAF mutations, younger age, and improved prognosis in GBM patients. However, further research is necessary to fully understand this correlation and its underlying mechanisms. While some studies have reported a positive correlation between
BRAF mutations and patient survival [
9,
30,
31,
32], others have observed contrasting results. For instance, Wang et al. [
34] found
BRAF mutations in a high percentage (80%) of their GBM samples and linked them to a significant decrease in survival [
34].
3.3. EGFR
The epidermal growth factor receptor (EGFR) is a transmembrane protein encoded by a gene located on the short arm of chromosome 7 at 7p11.2 [
35]. EGFR belongs to the ErbB receptor group, which consists of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4).
Under physiological circumstances, EGFR is essential for the ductal development of the mammary gland. EGFR agonists such as amphiregulin, TGF-α, and heregulin induce ductal and lobuloalveolar development, even in the absence of estrogen and progesterone [
36].
EGFR mutations affecting the expression of this gene can lead to uncontrolled cell growth and cancer [
37].
EGFR mutations leading to its overexpression or amplification are associated with a number of cancers and are often observed in GBM [
38]. However, targeted therapy against EGFR has not yet shown any clear clinical benefit. Several factors, including limited blood–brain barrier penetration, tumor cell diversity within the mass (intratumoral heterogeneity), and activation of alternative signaling pathways, can all contribute to the tumor’s resistance to this treatment [
39].
EGFR amplifications, commonly observed in GBM, have been shown by Matini et al. to promote angiogenesis and vascular proliferation within the tumor [
40] and are associated with poor survival [
40,
41]. Drugs that could block the EGFR pathway could, therefore, be useful in the treatment of GBM [
40].
While research by Matini et al. [
40] highlights the potential role of
EGFR amplification in GBM progression, other factors also influence patient outcomes. Armocida et al. [
42] conducted a retrospective study to evaluate the prognostic impact of
EGFR amplification in wild-type GBM samples of children and adults [
42]. They compared the amplification of
EGFR with various clinical factors, including patient age, tumor volume, and overall survival. Interestingly, their findings revealed a strong correlation between patient age and tumor volume with overall survival, suggesting these factors may be more significant prognostic indicators [
42].
Our analysis, along with findings from studies by Munoz-Hidalgo et al. [
43] and Schaff et al. [
44], consistently points towards a negative impact of
EGFR alterations on glioblastoma patient outcomes. Munoz-Hidalgo et al. [
43] observed poorer survival in patients with confirmed
EGFR amplifications [
43], and Schaff et al. [
44] identified a significant correlation between
EGFR amplification and
MGMT methylation status, which can influence treatment response [
44].
A study by Weller et al. [
45] investigated whether adding the vaccine rindopepimut to standard temozolomide chemotherapy could improve patient outcomes in newly diagnosed GBM. Unfortunately, the study found no significant impact of rindopepimut on overall survival in these patients [
45].
Targeted immunotherapy holds promise as a future treatment strategy for GBM, but further research is needed to realize its full potential.
3.4. IDH1, IDH2
Isocitrate dehydrogenase is an enzyme that catalyzes the reversible oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) as part of the tricarboxylic acid cycle in glucose metabolism in cells. This step also allows for the simultaneous reduction of nicotinamide adenine dinucleotide phosphate (NADP
+) to reduced nicotinamide adenine dinucleotide phosphate (NADPH) [
46]. It is, therefore, involved in energy metabolism.
IDH1 is located on the long arm of chromosome 2 at 2q34, while IDH2 is on the long arm of chromosome 15 at 15q26.1.
Because NADPH and α-KG have detoxification functions in the cell in response to oxidative stress, IDH1 is also indirectly involved in alleviating oxidative damage. In addition, IDH1 is key to the β-oxidation of unsaturated fatty acids in liver cell peroxisomes and is also involved in the regulation of glucose-induced insulin secretion [
47,
48]. Notably, IDH1 is the primary producer of NADPH in most tissues, especially in the brain. IDH2 has similar functions.
Mutations in the
IDH gene, specifically those affecting arginine residue R132, which are the most common, lead to a reduced ability to convert isocitrate to ketoglutarate, thereby reducing levels of ketoglutarate and NADPH, making a cell more sensitive to oxidative stress [
49]. Alteration of the enzyme’s binding site results in loss of normal enzymatic function and abnormal production of 2-hydroxyglutarate (2-HG), which inhibits the enzymatic functions of many alpha-ketoglutarate-dependent dioxygenases. These include histone and DNA demethylases. Consequently, their inhibition results in extensive changes in histone methylation and DNA itself and thus promotes tumorigenesis [
50,
51].
Mutations in the
IDH1 and
IDH2 genes strongly correlate with the development of glioma, acute myeloid leukemia, chondrosarcoma, intrahepatic cholangiocarcinoma, and angioimmunoblastic carcinomas of T-cell lymphomas [
52]. Tumors of various types with
IDH1/2 mutations show better responses to radiotherapy and chemotherapy [
53,
54].
The 2021 revision of the World Health Organization (WHO) classification system for central nervous system tumors reclassified IDH-mutant glioblastoma as IDH-mutant astrocytoma, WHO grade 4. This distinction reflects the improved prognosis associated with IDH mutations, as these tumors typically exhibit a better response to radiotherapy and chemotherapy compared to their IDH-wild-type counterparts.
IDH1 mutation is found in 5.6–12% of patients with gr. 4 astrocytoma. Chen et al. [
55] evaluated
IDH1 mutations in a sample of 1011 astrocytomas (previously glioblastomas).
IDH1 mutation was detected in 570 patients. Patients with proven
IDH1 mutation were found to have a better prognosis, with a median survival of 1.1–3.7 years [
55].
Emerging evidence from various research groups suggests a positive association between
IDH mutation status and improved clinical outcomes, particularly in terms of extended overall survival rates, for grade 4 astrocytoma patients [
54,
56,
57,
58].
3.5. MGMT
The MGMT gene is located on the long arm of chromosome 10 at 10q26.3. This gene encodes O-6-methylguanine-DNA-methyltransferase, an enzyme important for genome stability. It repairs damaged guanine nucleotides by transferring the methyl group at the O6 guanine site to its cysteine residues, thus preventing gene mutation, cell death, and tumorigenesis caused by alkylating agents. It removes alkaline groups, which are an important part of guanine methylation, from guanine. Therapy with the alkylating cytostatic drug temozolomide is based on this principle, assuming that the methylated form is nonfunctional.
MGMT methylation is observed in patients with glioblastoma [
59] but more often in anaplastic oligodendrogliomas [
60]. Studies have shown a positive effect of proven methylation of the
MGMT promoter in patients with high-grade glioma on the overall prognosis [
61,
62,
63,
64,
65,
66,
67,
68].
MGMT promoter methylation is, therefore, an important genetic alteration that has received significant research attention. It is associated with a more favorable response to temozolomide, a standard chemotherapy drug used for GBM [
69,
70].
Li et al. [
71] investigated a group of GBM patients who received temozolomide therapy and categorized them based on treatment response (progression, non-progression, pseudo-progression). Notably,
MGMT promoter methylations were more prevalent in the pseudo-progression group, where initial scans suggest tumor growth but may not reflect true tumor recurrence. This finding suggests that
MGMT methylations might be associated with a pseudo-progression phenomenon, requiring careful monitoring to avoid unnecessary treatment changes. Interestingly, the pseudo-progression group also exhibited a longer average survival time compared to the early-progression group [
71].
Correlations between
MGMT promoter methylation and
TERT mutations were the focus of other studies [
72,
73,
74]. Arita et al. [
72] showed worse outcomes in
TERT-mutant GBMs lacking
MGMT methylation. Similarly, Vuong et al. [
73] reported a survival benefit associated with
TERT mutations only in
MGMT-methylated tumors via meta-analysis. Shu et al. [
74] identified
MGMT methylation and
TERT mutations as independent prognostic factors, with these alterations, along with clinical features, forming distinct prognostic subgroups.
3.6. PIK3CA
PIK3CA is a gene located on the long arm of chromosome 3 at 3q26.32 and encodes phosphatidylinositol-3-kinase (also referred to as p110α). Phosphatidylinositol-3-kinases belong to the group of lipid kinases and are responsible for phosphorylating the 3-OH residue of the inositol ring of phosphoinositides, thereby being involved in the coordination of various cellular functions, including proliferation.
The
PIK3CA gene has been shown to be oncogenic and involved in the pathophysiology of cervical, breast, and colorectal cancer [
75]. Gallia et al. [
76] have shown that
PIK3CA mutations occur in a large number of glioblastoma patients and are, therefore, of therapeutic importance [
76].
McNeill et al. [
77] demonstrated that
PIK3CA mutations are limited to three functional domains: the adapter binding domain and the helical and kinase domains. Defining how these mutations affect gliomagenesis and the response to kinase inhibitor therapy (PIK3i, MEKi) may help in the development of new targeted therapies in patients with GBM [
77].
Tanaka et al. [
78] observed activating mutations in the
PIK3CA gene in 6–15% of glioblastomas. They retrospectively analyzed a group of 91 patients with GBM, with a mean age of 58 years (23–85), median PFS of 11.9 months, and median overall survival of 24 months [
78]. Thirteen patients (8.3%) had a proven
PIK3CA mutation.
PIK3CA mutation was associated with younger age (mean 49.4 years) and correlated with shorter PFS (6.9 months) and shorter overall survival (21.2 months). An association between
PIK3CA mutation and multiple disseminated disease, multiple lesions, or leptomeningeal spreading was observed in 46.2% of patients [
78].
3.7. PIK3R1
PIK3R1 is a gene located on the long arm of chromosome 5 at 5q13.1. It has similar functions as PIK3CA. It encodes a phosphatidylinositol-3-kinase and plays an important role in the metabolic action of insulin. Mutations in the gene are associated with insulin resistance.
Mutations in the
PIK3R1 gene have been addressed by Quayle et al. [
79]. The authors found that mutations in the iSH2 pathway of PIK3R1 trigger oncogenic activity, and thus, patients with proven
PIK3R1 mutation can benefit from treatment with AKT inhibitors [
79]. Somatic mutations in
PIK3R1 are observed in many types of tumors.
The tumorigenic activity of
PIK3R1 has been demonstrated in GBM. Weber et al. [
80] mapped changes in the
PIK3CA and
PIK3R1 genes. They found that eliminating either of these genes alone in GBM cell lines by lentivirus-mediated shRNA expression resulted in reduced proliferation, migration, and invasion in all the cells tested [
80].
Mutations in
PIK3CA and
PIK3R1, key components of the PI3K signaling pathway, are emerging as potential therapeutic targets in GBM due to their critical role in regulating cell growth and activity [
80].
3.8. PTEN
The
PTEN (phosphatase and tensin homolog) gene is located on the long arm of chromosome 10 at 10q23.3. It encodes a protein with phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity, the activity of which attenuates AKT/PKB cascade signaling. It is thus a tumor suppressor gene and is currently the target of many anti-cancer drugs [
81].
PTEN gene mutations are especially involved in the pathophysiology of glioblastomas and lung, breast, and prostate tumors [
81].
Koshiyama et al. [
82] evaluated
PTEN and
TP53 mutations in a cohort of 40 glioblastoma patients with a median age of 59.3 years (range 41–83 years) and a male predominance (70%). The median survival was 145 days.
EGFR amplification was detected in 42.5%,
PTEN deletion in 35%, and
TP53 deletion in 22.5% of patients. Notably, confirmed
TP53 and
PTEN mutations were associated with a poorer prognosis [
82].
Xu et al. [
83] investigated the influence of
PTEN mutations on progression-free survival (PFS) in a larger cohort of 586 GBM patients.
PTEN mutation status is recognized as a factor affecting treatment response and relapse risk. Among
PTEN mutations, the authors describe missense, nonsense, frameshift, and other types of mutations [
83]. Their frequencies and associated PFS are detailed in
Table 1.
Analysis of
PTEN mutations in glioblastoma patients reveals a potential link between mutation type and prognosis, as reported by Xu et al. [
83]. Their study demonstrates that nonsense mutations have a more significant negative impact on progression-free survival compared to other mutation types (potentially associated with
PTEN overexpression). The median PFS for patients with nonsense mutations was 3.8 months, whereas patients with other mutation types exhibited a median PFS of 7.2 months. Interestingly, missense/frameshift mutations did not appear to have a substantial influence on PFS. These findings suggest that the specific type of
PTEN mutation may influence patient outcomes [
83].
Overall, the presence of a
PTEN mutation, regardless of type, has been associated with a decrease in PFS by up to 50% [
83]. This highlights the potential prognostic value of
PTEN mutation analysis in GBM patients.
Carico et al. [
84] investigated the potential association between
PTEN mutation status and overall survival in GBM patients. Their study included 155 patients, with 65% harboring confirmed
PTEN mutations. The
PTEN-mutant group had a mean age of 63 years, and 70% of patients scored above 80 on the Karnofsky Performance Scale (KPS), indicating a good performance status. Although no significant associations were found between individual patient criteria and
PTEN mutation or its overexpression alone, patients with
PTEN deletion were generally older, had a higher degree of neurological impairment, and were undergoing a less extensive surgical resection. The authors further analyzed the impact of various characteristics potentially linked to
PTEN status on overall survival. Details regarding these characteristics and their association with OS are presented in
Table 2 of the original study [
84].
Younger patients (under 65 years old) with a higher KPS score (over 80) and a large extent of resection (total or gross total resection) are important predictors of further patient survival [
84].
The prognostic significance of
PTEN mutations in glioblastoma remains a topic of ongoing investigation, with conflicting results reported in the literature. Several studies, including those by Kraus et al. [
85], Tadipatri et al. [
86], and Ermoian et al. [
87], have identified
PTEN mutations as a negative prognostic factor, associating them with shorter survival times [
85,
86,
87]. For instance, Ermoian et al. reported a median survival of 195 weeks (10–411) in glioblastoma patients with
PTEN mutation [
87].
However, other studies have challenged this association. Ruano et al. [
88] did not observe a significant impact of
PTEN mutation on prognosis, suggesting that mutations in
EGFR and
TP53 might be more relevant for predicting survival. Their study reported a median overall survival of 10 months for the entire glioblastoma patient cohort [
88]. Backlund et al. [
89] also reported a median survival of 437 days in their group of GBM patients, with
PTEN-mutant glioblastoma having a median survival of 166 days [
89].
These contrasting findings highlight the complexity of PTEN mutations and their potential interaction with other genetic alterations in influencing GBM prognosis. Further research is necessary to elucidate the precise role of PTEN mutations and identify robust prognostic markers for GBM patients.
3.9. TERT
Telomerase reverse transcriptase (TERT) is a catalytic subunit of the telomerase enzyme. The TERT gene is on chromosome 5.
Reverse transcriptases are enzymes that catalyze the process of transcribing genetic information from ribonucleic acid (RNA) to deoxyribonucleic acid (DNA). In practice, it is most often part of the transmission of the genetic code of a retrovirus such as HIV to the host infected cells’ DNA. Telomerase lengthens telomeres in DNA strands, allowing aging cells that would otherwise undergo apoptosis to exceed the Hayflick limit and become potentially immortal, as we often see in tumor cells. Almost all GBM show telomerase activity, which is a major agent in achieving cell immortalization [
90].
If a correlation between increased telomerase activity and malignancy is demonstrated, the inhibition of the enzyme could induce cell aging and, thus, apoptosis, which could be used in therapeutic practice. Confirmed TERT mutation correlates with poorer survival rates.
Nonoguchi et al. [
91] investigated the co-occurrence of genetic alterations in GBM, finding a correlation between
TERT promoter mutations and mutations in
IDH1,
TP53, and
EGFR amplification. Interestingly, their analysis of 358 GBM samples revealed a mutually exclusive relationship between
TERT and
IDH mutations, with co-occurrence detected in only a small percentage (3%) of patients [
91].
TERT expression can be altered by activating mutations in the rs2853669 polymorphism in the promoter region. Spiegl-Kreinecker et al. [
92] investigated the prevalence of
TERT promoter mutations in a cohort of 126 GBM samples. A high frequency (73%) of
TERT promoter mutations was identified. Among these mutations, C228T and C250T were the most common, detected in 66 and 26 patients, respectively. Details regarding the distribution of other mutation types are presented in
Table 3 of the original study [
92].
Spiegl-Kreinecker et al. [
92] also investigated the rs2853669 single nucleotide polymorphism (SNP) within the
TERT promoter region. Analysis of their GBM samples revealed that 59 patients (45%) did not harbor this polymorphism, while 67 (53%) did. Interestingly, among the 67 patients with the polymorphism, 12 possessed the homozygous CC genotype, and 55 exhibited the heterozygous CT genotype. Further details regarding the distribution of other genotypes, if any, are found in
Table 4 of the original study [
92].
The authors did not find a significant correlation between the mutation status of the
TERT promoter and rs2853669 polymorphism. Proven
TERT mutation negatively affected prognosis and shortened survival time, especially in the group of patients over 65 years of age. In agreement with Nonoguchi et al. [
91], they found
TERT and
IDH1 mutations to be mutually exclusive [
91].
Mosrati et al. [
93] evaluated
TERT promoter mutations and rs2853669 polymorphism in GBMs. The mutation C228T was confirmed in 75% and C250T in 25% of patients. The overall survival time of a patient with proven
TERT promoter mutation was 11–20 months [
93].
Similarly, other authors, including Simon et al. [
94], describe
TERT mutation as a negative prognostic marker [
94]. In their group of 147 patients with IDH-wild-type GBM, Kikuchi et al. [
95] confirmed
TERT mutation in 92 patients (62.6%). The median age at diagnosis was 66 years, and patients with
TERT mutation had a shorter PFS (7–10 months) [
95].
Promoter mutations (particularly in the
TERT promoter) are associated with increased telomerase activity. Fan et al. [
96] demonstrated that there are alternative pathways to telomere extension in GBM and that these correlate with
ATRX mutations. Mutations in
TERT (telomerase reverse transcriptase promoter) and
ATRX may allow tumor cells to escape apoptosis [
96].
3.10. TP53
The
TP53 gene is located on human chromosome 17p13.1. It encodes the p53 protein that consists of 393 amino acids [
97,
98]. The tumor suppressor and transcription factor p53 plays critical roles in tumor prevention by orchestrating a wide variety of cellular responses, including damaged cell apoptosis, maintenance of genomic stability, inhibition of angiogenesis, and regulation of cell metabolism and tumor microenvironment [
98]. The importance of the
Tp53 gene as a tumor suppressor is highlighted in human cancer, where it is the most commonly mutated gene [
99]. The p53 pathway is also frequently deregulated in GBM [
98]. In primary and secondary GBM, TP53 mutation is observed in up to 30% and 70% of cases, respectively, which results in a common molecular abnormality linked to a worse prognosis [
100]. Wang et al. [
101] confirmed that
TP53 mutations are associated with poorer prognosis and shorter survival time in patients with GBM. In addition,
TP53 mutation may reduce the chemosensitivity of GBM to temozolomide by increasing
MGMT expression [
101].
Investigating the prevalence of
TP53 mutations in GBM, Homma et al. [
102] identified
TP53 mutations in 113 out of 420 patients (26.9%). Interestingly, they observed a correlation between
TP53 mutations and a specific GBM subtype—giant-cell glioblastoma, characterized by atypical large cells with multilobed nuclei. Notably,
TP53 mutations were detected in 78% of giant-cell GBM cases. Conversely, TP53 mutations were not found in necrotic GBM [
102].
Their analysis also revealed an association between
TP53 mutations and patient characteristics. Patients with
TP53 mutations tended to be younger and have secondary GBM (arising from pre-existing lower-grade gliomas) compared to those without the mutation proven [
102].
Furthermore, the study explored the potential prognostic value of
TP53 mutation status. They divided patients into two groups based on survival: long-term survivors (over 3 years after surgery) and short-term survivors (under 1.5 years after surgery). Patients with higher p53 expression, a protein encoded by the
TP53 gene, were found in the long-term survival group (85%), compared to 56% in the short-term survival group [
102]. These findings suggest a potential link between p53 expression and improved survival in GBM patients, warranting further investigation.
Cantero et al. [
103] analyzed the genetic profiles of 36 glioblastoma patients. p53 expression was detected in all samples.
BRAF and
H3F3A mutations were uncommon or not detected at all. A set of 36 GBM samples was divided into two groups: wild-type GBM (wt-GBM) and giant-cell GBM (gc-GBM). In the giant-cell GBM group, the frequencies of p53 expression and
ATRX,
RB1, and
NF1 mutations were higher, while
EGFR amplification,
CDKN2A deletion, and
TERT mutations were less frequent. Patients with gc-GBM with proven
TP53 mutation were found to have better survival rates than patients with wt-GBM and
TP53 mutation. gc-GBM has different molecular properties than wt-GBM, in addition to unusually common
ATRX mutations,
EGFR amplifications, and
CDKN2A deletions [
103].
Out of a group of 301 patients with GBM, Weller et al. [
104] reported
TP53 mutation in 15%; the overall outcome was not affected by the presence/absence of
TP53 mutation [
104].