The Place and Prognostic Value of TERT Promoter Mutation in Molecular Classification in Grade II-III Glial Tumors and Primary Glioblastomas
Neslihan Kaya TERZI1, Ismail YILMAZ2, Aysim Buge OZ3
1Department of Pathology, University of Health Sciences Gaziosmanpasa Research and Training Hospital, ISTANBUL, TURKEY
2University of Health Sciences, Sultan 2. Abdulhamid Han Research and Training Hospital, ISTANBUL, TURKEY
3University of Cerrahpasa, Cerrahpasa Medical Faculty, ISTANBUL, TURKEY
Keywords: Diffuse glioma, Primary glioblastoma, TERT p, Promoter mutation, Survival
Diffuse gliomas, the most common primary malignant brain tumors, have been classified by the World Health Organization as class
II-IV gliomas. After 2016, two mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene were identified in addition
to the IDH, 1p / 19q, and ATRX status.
Material and Method: We identified 84 patients with grade II-IV glioma with IDH, ATRX, 1p / 19q and TERT status. All tumor samples were
subjected to molecular genetic screening (Sanger sequencing for IDH and TERT mutations, fluorescence in situ hybridization for 1p/19q status)
after histological diagnosis (immunohistochemistry for IDH1 R132H, ATRX, and p53) for a more precise molecular diagnosis. The confidence
intervals were calculated at the 95% confidence level, and differences at p < 0.05 were considered statistically significant.
Results: Primary glioblastomas had the highest frequency of TERT promoter mutations (25 of 28, 89.2%, p=0.006) followed by oligodendrogliomas
(29 of 35, 82.8%, p<0.001) while astrocytomas showed the lowest frequency (3 of 15, 20%, p=0.107), and the positivity significantly differed
among these three groups (p<0.001). TERT promoter mutations were more frequent in patients older than 55 years of age at diagnosis (p=0.023).
The group with TERT promoter mutations, and without IDH mutations showed the worst overall survival. However, the presence of both TERT
promoter and IDH mutations, which resembled oligodendroglial progression, showed best overall survival (p=0.042).
Conclusion: The discovery of TERT promoter mutations in numerous gliomas has opened the door for a better molecular classification of
gliomas, and TERT status is associated with survival. Further studies will help in elucidating the value of TERT promoter mutations as biomarkers
in clinical practice, and eventual therapeutic targets.
Diffuse gliomas, the most common primary malignant
brain tumors, have been classified by the World Health
Organization (WHO) as class II-IV gliomas 1
2016, increasing and broad characterization of the
genomic structure of gliomas has led to the identification
of genetic and epigenetic markers useful for the molecular
classification of these tumors 2
. In addition to the IDH,
1p / 19q, and ATRX status, two mutations in the promoter
region of the telomerase reverse transcriptase (TERT) gene
were frequently identified 3
. The mutation in the promoter
region of this gene was first discovered in melanoma 4
In 2013, TERT promoter mutations were included in
the molecular classification of gliomas 3
. TERT is an
important unit of the telomerase complex. It is known
that upregulation of TERT increases telomerase activity,
the basic survival ability of cancer cells, which allows for unlimited expansion of telomeres, and immortalization
of cells 5
. The mutation takes place in one of the two
hot spots of the TERT gene, C228T and C250T, as C-T
TERT mutations are usually investigated by sequencing
or real-time PCR 7, and TERT promoter mutations
occur in 70-80% of glioblastomas (GBM), 95% of
oligodendrogliomas (OD), and 10-25% of astrocytomas
5. TERT promoter mutations are significantly inversely
proportional to IDH1 / 2 mutations 8. Changes in TERT
and IDH are not only associated with specific histological
glioma subgroups, but also are associated with a variable
The literature on telomere-related mechanisms with glioma
is rapidly increasing. Their prognostic and predictive roles
are very interesting and may guide the clinical management of glioma patients. Yet, there are no studies investigating the
distribution and significance of TERT promoter mutations
in the WHO 2016 classification 10.
In the study conducted at Mayo Clinic, cases with 1 / 19q
co-deletion, IDH mutation and TERT promoter mutation
(triple-positive) were associated with an oligodendroglial
phenotype and showed better overall survival (OS). Lowgrade
tumors (II and III) showing TERT and IDH mutations
without 1p19q co-deletion tended to have a prognosis
similar to triple-positive cases 11. However, patients
without TERT and IDH mutations and those with 1p/19q
co-deletion had very aggressive tumors and poor survival.
Patients with wild-type (WT) TERT, IDH, and persevered
1p19q (triple negative) were associated with GBM, and
had worse prognosis than triple-positive gliomas, but had
a better prognosis than in patients with TERT mutations
This study was approved by the medical ethics committee
of the University of Health Sciences, Samatya Training
Hospital (Approval No.: 06.07.2018 / 1337), and it was
conducted according to the Declaration of Helsinki
We identified 84 patients (32 females and 52 males) with
grade II-IV glioma with known IDH, ATRX, 1p / 19q
and TERT status. Fifty-seven patients had WHO grade
II-III tumors (24 oligodendrogliomas (OD), 14 anaplastic
ODs, 13 astrocytomas, 5 anaplastic astrocytomas, and
1 anaplastic oligoastrocytoma with a low grade glioma
component), and the remaining 27 samples represented
high grade glioma (WHO grade IV/GBM) (Table I).
Click Here to Zoom
|Table I: Clinicopathological variables of the 84 diffuse glioma
All tumor samples were subjected to molecular genetic
screening after histological diagnosis for a more precise /
molecular diagnosis 13,14. Tumors in the astrocytoma
group were characterized by detectable immunoreactivity
for IDH1 (R132H), p53 and loss of immunoreactivity
for ATRX 15. All tumors in the OD group had IDH1
mutation (R132H) and 1p / 19q co-deletion. GBMs were
IDH wild type (IDH-WT) 1.
Immunohistochemistry (IHC), Assessment of TERT
promoter and IDH Mutation, Fluorescence in situ
Immunohistochemistry (IHC) was performed on at least
one representative block using primary antibody against
the following antigens- IDH1 R132H (Dianova, dilution
1:40), ATRX (Sigma, dilution 1:300), and p53 (Dako, dilution 1:50). Cases showing cytoplasmic positivity for
IDH1 in tumor cells were considered positive. Loss of
nuclear staining for ATRX in tumor cells (>90%) was
considered positive for ATRX mutation. Nuclear positivity
for p53 in >10% tumor cells was considered positive 16.
Mutations in the promoter region of TERT gene (chr5,
1,295,228C>T and 1,295,250C>T) and exon 4 of IDH1
and IDH2 genes (well-known hotspot regions for
oncogenic mutations) were analyzed by PCR-based
direct sequencing using representative formalin-fixed
paraffin-embedded tumor samples. Tumor targets were
manually microdissected from 5-μm thick unstained
histological sections. After deparaffinization and
rehydration, DNA was isolated from each target using
QIAamp DNA FFPE Tissue Kit (50) (catalog #: 56404)
(QIAGEN, Hilden, Germany) in accordance with the
manufacturer’s instructions. DNA concentrations of
samples were assessed spectrophotometrically using a
Nanodrop 1000 spectrophotometer (Thermo Scientific,
USA). PCR was performed in a Thermal Cycler (ABI,
Applied Biosystems, USA) using HotStarTaq DNA
Polymerase kit (catalog #: 203205) (QIAGEN, Hilden,
Germany), and appropriate primers (TERT -Forward:
5’CAGCGCTGCCTGAAACTC’3, TERT -Reverse:
5’GTCCTGCCCCTTCACCTT’3, IDH1 exon 4-Forward: 5’
CCAAGTCACCAAGGATGCTG’3, IDH1 exon 4-Reverse:
5’ TCACATTACTGCCAACATGACTT’3, IDH2 exon
4-Forward: 5’ CCGTCTGGCTGTGTTGTTG’3, and IDH2
exon 4-Reverse: 5’ AGTCTGTCGCCTTGTACTGC’3).
PCR reactions were run as total volume of 50 μl reaction
mixtures consisting of nuclease free water, 5 μl 10x PCR
Buffer, 10 μl Q solution (for TERT), 1.5 μl 10 mM dNTP
mix (ABI, Applied Biosystems, USA), 2 μl 25 mM MgCl2
(for IDH1 and IDH2), 7 μl (for TERT) and 6 μl (for IDH1
and IDH2) of each primer (4pmol/μl), 0.25 μl of Hot Start
Taq DNA polymerase, and 50 ng of each tumor DNA.
After an initial denaturation at 95°C for 15 minutes, 42
cycles were performed of 30 seconds denaturation at 95°C,
30 seconds annealing at 55°C (for TERT), and at 58°C
(for IDH1 and IDH2), and 45 seconds extension at 72°C,
followed by a final extension of 10 minutes at 72°C. The
intensity of the PCR products were checked by running 5
μl of each PCR reaction with 2 μl of loading dye on a 2%
agarose gel. Reagent contamination control was achieved
by examining the lane for “No DNA” blank tube. Then, all
succeeded PCR products were purified using the QIAquick
PCR Purification Kit (catalog #: 28106) (QIAGEN, Hilden,
Germany) according to the manufacturer’s instructions.
The purified amplicons were submitted to direct sequencing
in both directions (forward and reverse) using reagents
from the Big Dye Terminator v3.1 Cycle Sequencing kit
(ABI, Applied Biosystems, USA) in accordance with the
manufacturer’s protocol. After ethanol precipitation,
subsequent products were run on the ABI-3730 (48
capillary) automatic sequencer (Applied Biosystems, USA). Bidirectional sequence traces were analyzed with SeqScape®
Software v3.0 (Applied Biosystems, USA), and manually
FISH analysis was performed on 5-micron-thick formalin
fixed paraffin-embedded tissue samples. Deparaffinization,
pre-hybridization and hybridization steps were conducted
according to the datasheet. One hundred tumors cells were
analyzed on the fluorescent microscope (Olympus BX61;
Olympus Optical, Japan). The cells were captured on a
computer system with a digital camera (XLMM, Dage-
MTI, IN, USA), and compatible software (Duet®, Bioview
Ltd., Israel). Dual-color paired probes for 1p and 1q (1p36
Spectrum Orange and 1q25 Spectrum Green, Vysis LSI
probes, Abbott Molecular, Des Plaines, IL) were hybridized
simultaneously on one slide, and similarly those for 19q,
and 19p (19q13 Spectrum Orange and 19p13 Spectrum
Green, Vysis LSI probes, Abbott Molecular, Des Plaines,
IL) were used on a separate slide. A proportion is used due
to the fact that a significant number of nuclei would have
reduced comparison/control (green) signals because of
tissue sectioning removing portions of the nuclei. Based on
laboratory experience, a proportion <0.80 was considered as
a deletion. The ratio of SpectrumOrange to SpectrumGreen
signals (total orange/total green) was calculated.
Statistical analyses were performed using IBM SPSS
Statistics for Windows, Version 21.0. (IBM Corp., Armonk,
NY). Descriptive statistics were used to describe the data.
Normal distribution was tested by the Kolmogorov-
Smirnov and Shapiro-Wilk tests. Non-parametric data were
compared using the Chi-square test. The Kaplan-Meier
method was used for survival analysis, and the log-rank
test (Mantel-Cox) was performed to compare the survival
curves between the groups. The confidence intervals were
calculated at the 95% confidence level and differences at p
<0.05 were considered statistically significant.
A total of 84 patients consisting of 52 men (61.9%) and 32
women (38.1%) were recruited. Their mean age was 44.68
± 14.12 years (range 12–82 years). The mean duration
of follow-up was 24-60 months. There were 65 patients
(77.3%) aged less than 55 years, and 19 patients (22.6%)
older than 55 years. The WHO 2016 revised diagnosis of
the study group was as follows: 10 diffuse astrocytomas -
IDH-mutant (11.9%); 3 diffuse astrocytomas- IDH-WT
(3.5%); 4 anaplastic astrocytomas- IDH-mutant (4.7%);
23 ODs-IDH-mutant, and 1p/19q codeleted (27.3%); 14 anaplastic ODs, IDH-mutant & 1p/19q-codeleted (16.6%);
1 OD NOS (1.1%); 1 anaplastic oligoastrocytoma (1.1%),
and 28 GBM-IDH-WT (33.3%). Biopsy was carried out
only in 10 patients (11.9%), and debulking surgery was
performed in 74 patients (88%). 80 patients (95.2%) were
treated with some form of adjuvant radiotherapy and/
or chemotherapy, while 4 (4.7%) patients did not receive
any adjuvant radio-chemotherapy. 61 patients were alive
(72.6%) while 19 patients (22.6%) died (Table I
TERT Promoter Mutations and Alterations in
Overall, TERT promoter mutations were present in 57
of 84 (67.9%) gliomas [20 (60.6%) in grade II, 12 (66.6%)
in grade III, and 25 (92.5%) in grade IV]. The C228T
mutation was detected in 42 tumors (53.8%), whereas the
C250T mutation was found in 15 cases (19.2%), supporting
the predominance of the C228T mutation in glioma.
Primary glioblastomas had the highest frequency of TERT
promoter mutations (25/28; 89.2%, p=0.006) followed
by oligodendrogliomas (29/35; 82.8%, p<0.001), while
astrocytomas showed the lowest frequency, with 3 out of
15 (20%, p=0.107) samples showing mutations (Table II).
TERT promoter mutations were found to be associated
with high grade (grade III/IV) tumors when compared to
lower grade (grade II) lesions (p<0.033), and were more
frequent in patients older than 55 years of age (p=0.023).
A statistically significant association was observed between
the TERT mutation and the diagnosis (p<0.001). We
performed post hoc power analysis by G*Power 22.214.171.124.
The Type II error (β) probability was less than 0.01 (power
>0.99) for the combined diagnostic algorithm (Figure 1).
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|Figure 1: Specificity and sensitivity of TERT mutation in glioblastoma, oligodendroglioma / anaplastic oligodendroglioma, and
astrocytoma / anaplastic astrocytoma.
IDH gene mutations were present in 44 tumors (42 of
these being IDH1 R132H mutations). Twenty-nine of
these (corresponding to oligodendrogliomas) harbored a
concomitant 1p/19q co-deletion, and all of them except
three were also TERT promoter mutant.
The TERT p mutation and IDH mutation were more highly
associated compared to TERT p with IDH-WTs (P<0.001
and p=0.655, respectively). However, in oligodendroglial
tumors, TERT promoter and IDH mutations occurred
together (p<0.001). 24 of 26 IDH/TERT double
mutant tumors had the 1p/19q co-deletion. In primary
glioblastomas, there were no IDH mutations, as expected.
In astrocytomas, TERT promoter and IDH mutations were
both found in only 2 of 15 cases (Figure 2).
Click Here to Zoom
|Figure 2: Molecular classification of diffuse glioma and frequency of each subgroup in our study.
Moreover, TERTp and TP53 mutations in low-grade and
anaplastic gliomas were mutually exclusive, where none and
5.5% of TERT mutated tumors harbored TP53 mutations,
respectively. A statistically significant association was
observed between the TERT mutation and p53 mutation
TERT promoter mutations were mutually exclusive with
ATRX deficiency. However, no statistically significant
association was observed between the TERT mutation and
ATRX mutation (p=0.533).
Effect of TERT Promoter Mutations on Survival
Results of the Kaplan-Meier survival analysis are shown in
Click Here to Zoom
|Figure 3: Survival
times of anaplastic
and glioblastoma cases
(A). Survival times
of cases with TERT mutation (B).
The overall cumulative survival in cases with TERT
mutation was 64.94 months (95% CI=55.58-74.31) and
overall cumulative survival in cases without TERT mutation
was 46.80 months (95% CI=37.71-55.89) (p=0.870) (Figure
3B). Patients carrying the C250T mutation had slightly
longer survival compared to patients with the C228T
mutation (78.5% and 76.9%).
Moreover, the TERT mutation frequency, both C228T
and C250T, increased with age: <40 years: 65.5% (19/29);
40-55 years: 66.6% (20/30), and >55 years: 94.7% (18/19).
Compared to patients with WT- TERT, younger patients
with TERT mutation survived longer, but patients with
TERT mutation who were aged >55 years had shorter
Stratification of the patients based on the mutational status
of TERT promoter and IDH resulted in three groups with
different overall survival. The group with TERT promoter
mutations and no IDH mutations had the worst overall
survival (median survival 12.29 months), the 2nd worst
overall survival rate was the group without TERT and
IDH mutations (median survival 24 months). Best overall
survival was associated with the presence of both TERT
promoter and IDH mutations (median survival 38.07
months), which resembles oligodendroglial progression
Survival analysis in patients with primary glioblastomas
did not reveal any effect of the TERT promoter mutations.
Both patients with and without TERT promoter mutations
had a median survival of 12 months (Figure 3A).
In diffuse and anaplastic gliomas that showed TERT
promoter mutations were associated with poor survival
while 1p/19q co-deletions had a favorable effect. Survival
in gliomas with a TERT mutation and 1p19q co-deletion
(median survival 58.2 months) was higher than in those
without TERT mutation and 1p19q codeletion (median
survival 42 months).
Gliomas are the most common and aggressive primary
brain tumors in adults (2). For diffuse gliomas, IDH
mutations and 1p/19q co-deletion constitute the main
components of the integrated WHO 2016 diagnosis.
Molecular classifications proposed in the literature include
the combination of the IDH mutations, the 1 p / 19q codeletion,
and the telomere maintenance mechanism
as defined by alterations in TERT 15
. To determine
whether the TERT status provides additional prognostic
information, we analyzed the relationship between overall
survival in glioma patients classified according to the WHO
2016 criteria in our cohort.
Recent studies have shown that this classification has certain
limitations for precise prediction of clinical outcomes and
strategies for gene target therapy 16. Therefore, a more
objective glioma classification is needed to guide diagnosis
and treatment strategies.
Telomeres are structures at the end of eukaryotic
chromosomes and are responsible for the deterioration
of chromosomes, end-to-end fusion, and protection from
rearrangement 17. Telomerase maintains the appropriate
telomere length by adding repeated telomeric sequences to
the 3’ ends of the telomeres. Abnormal telomerase activity
plays a role in the initiation and development of cancer and
other diseases related to aging 18. TERT is overexpressed
in many human cancers 19. TERT promoter mutations
were first found in melanoma and were thought to represent
the tumorigenic mechanism 16.
The discovery of TERT p mutations in numerous gliomas
has opened the door for a better molecular classification of
gliomas in 2013 20,21. TERT promoter mutations occur
in 70-80% of glioblastomas, 95% of oligodendrogliomas,
and 10-25% of astrocytomas 5,7,11.
The prevalence of TERT promoter mutations associated
with various histological categories was similar to other
studies 22,23. As expected, IDH-mutant tumors were
prevalent predominantly in younger adults, while all
IDH-WT/ TERT -mutant tumors apart from a single
pediatric tumor occurred in adults. Our findings are
consistent with the concept that IDH-WT/ TERTmutant
diffuse gliomas represent a clinicopathological
part of primary glioblastomas and their precursors 24,25. In any case, inclusion of TERT promoter mutation
analysis into a diagnostic molecular panel shifts the vast
majority of otherwise marker-negative diffuse gliomas
into a biologically plausible category. Furthermore, TERT
promoter mutation status is of prognostic significance not
only in diffuse gliomas with non-glioblastoma histology
11,25, but also in glioblastoma 10,26. The present study
demonstrates that adding the TERT promoter mutation
status to standard markers, as suggested in the literature,
results in a precise molecularly directed classification with
IDH-WT/ TERT -mutant tumors representing the primary
glioblastoma group 27.
Age was another parameter for survival. Patients aged
>55 years who had TERT mutation had worse survival
compared to patients without the mutation.
In the whole cohort, patients with C250T mutations tended
to have longer survival compared to patients with C228T
mutations. We found that occurrence of the C228T and
C250T mutations were mutually exclusive in our cohort,
and that C228T (84.2%) was more common than C250T
With rare exceptions, TERT promoter mutations 8,
which lead to an increase in telomerase expression,
and inactivating mutations in the thalassemia/mental
retardation syndrome X-linked (ATRX) gene, are mutually exclusive, and are associated with different molecular
tumor subclasses 28. Our study was the exception for
mutual relationship of ATRX and TERT mutations, as
we could not find any significant relationship (p=0.533).
On the other hand, our study demonstrated that TERT
promoter mutations have a significant inverse association
with P53 mutation (p<0.001), similar to previous studies
TERT promoter mutations have been reported to be
associated with aggressive behavior and poor outcome in
various types of cancers 3. In this study, prognosis in
glioblastoma cases with TERT mutation was worse than
in oligodendrogliomas with TERT mutation. Cases with
TERT mutation had a worse prognosis than cases without
TERT mutation, but none of the relevant results in our
study had statistical significance.
The combination of TERTp and IDH mutational status was
a significant prognostic factor in grade II and III gliomas;
this finding of a specific association between IDH/ TERTp
group and low-grade glioma is consistent with results from
a previous study 20,29. Eckel-Passow et al. 12 showed
that patients with IDH-WT/TERTp-WT have poorer
overall survival when compared with patients with IDHmutated/
TERTp or IDH mutation alone, but showed better
overall survival when compared with patients with IDHWT/
TERTp-mutation 11. A recently published metaanalysis
also suggested that combined TERTp-mutated/
IDH-WT testing could act as a significant biomarker for
poor prognosis in grade II and III gliomas 20.
Given that 67.9% of tumours being TERTp-mut, TERT
is the most frequently mutated gene in gliomas thus
far identified 5,8,30-32. Our data confirm the high
frequency of TERTp-mutation in gliomas, and show
that these mutations clusterise into specific entities, with
distinct clinical significances.
In previous studies, the 1p/19q co-deletion was strongly
associated with mutations in TERTp 33,34. In the
present study, we found that 96.9% of patients with
oligodendrogliomas had a TERTp mutation, whereas two
patients with oligodendroglioma were TERTp-WT. On the
contrary, there was a high frequency of TERTp mutation in
cases with GBM that did not harbor the 1p/19q co-deletion,
and therefore we conclude that the TERTp mutation is not
exclusively associated with the 1p/19q co-deletion.
Regarding the TERTp mutation from a prognostic
perspective in diffuse gliomas, previous studies have shown
conflicting results. Labussiere et al. have found that TERTp
mutations may be associated with poorer outcome in highgrade gliomas 31, however, Pekmezci et al. have reported
that TERT-mutants had significantly worse survival only
in IDH-WT astrocytoma, which includes grades II and
III 10. Such contradictory effects of TERTp mutation
on patient outcome between groups have been reported
previously 11. Aibaidula et al. found comparable results
to those of Pekmezci et al., and concluded that adult IDHWT
lower-grade gliomas should be further classified by
TERTp mutation status 35.
According to Cimpact now update 3, IDH wild type diffuse
or anaplastic astrocytomas will have a worse prognosis as
grade IV glioblastomas. The following molecular methods
can be used to distinguish these cases: EGFR amplification,
losses of chromosome 10 (whole chromosome, 10p or
10q), gains of chromosome 7 (whole chromosome, 7p or
7q), TERT promoter mutations, homozygous deletion
of CDKN2A/B, and large-scale, microarray based DNA
methylation profiling. According to the results of the
current study, histologic IDH-wildtype diffuse astrocytic
gliomas of WHO grade II or III that carry EGFR
amplification, +7/−10 or TERT promoter mutation are
associated with significantly shorter survival compared
to patients with other WHO grade II or III gliomas, and
outcomes are similar to those in patients with IDHwildtype
glioblastoma 27. Molecular studies other than
TERT promoter mutation could not be performed, and this
is a limitation of our study. We aim to fill this gap in future
IDH mutation was detected in 16 cases with midline
localization in our study and their grade was II. In these
cases, which are known to have a good prognosis in followup,
diffuse midline glioma was evaluated by considering
it in the differential diagnosis. However, H3F3A K27M
mutation could not be detected with immunohistochemical
or molecular methods.
TERT promoter mutations were shown to have inverse
prognostic effects in IDH-mut and IDH-WT WHO grade
II/III gliomas. Our study strongly supports using TERT and
IDH genotyping in WHO grade II/III gliomas as a reliable
and reasonable test that can help clinicians predict patient
outcome more precisely than using only conventional
histology, or TERT or IDH status alone. It is important
to note that gliomas with concurrent TERT promoter and
IDH mutations are almost always accompanied with 1p19q
co-deletion, which is the hallmark of oligodendroglioma
according to the WHO classification 2016, and it can
help to explain why gliomas with coexisting IDH and
TERT promoter mutations are most likely associated with
Data suggest that patients with TERT promoter mutations
in tumors probably require more aggressive treatment than
their WT counterparts. Further studies will help elucidating
the value of TERT promoter mutations as biomarkers
in clinical practice and eventual therapeutic targets.
Expression data and an association with shorter telomeres
already strongly indicate the role of the TERT promoter
mutations not only in glioma, but in many other cancer
types, and future functional studies will aid in placing the
TERT promoter mutations into the right context.
CONFLICT of INTEREST
The authors declare that they have no conflict of interest.
This study was supported by the University of Health
Sciences Scientific Research Unit (Project number
The statistical part of the study was conducted by specialist
pediatrician doctor Ersin Tural.
Concept: NKT, IY, BO, Design: NKT, IY, BO, Data
collection or processing: NKT, Analysis or Interpretation:
NKT, IY, BO, Literature search: NKT, IY, BO, Writing:
NKT, IY, BO, Approval: NKT, IY, BO.
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