Download Analysis of isocitrate dehydrogenase mutations in gliomas

Analysis of isocitrate dehydrogenase1/2 gene mutations in gliomas
YU Lei, QI Song-tao, OU Yang-hui and LI Zhi-yong
Keywords: IDH mutation; Glioma;α-Ketoglutarate; 2-Hydroxyglutatarate; Hypoxia-inducible
factor
Objective
Gliomas are the most frequent, lethal, and rapidly infiltrating form of brain cancer
that is resistant to surgery, radiotherapy and chemotherapy. The molecular profiling of gliomas
genomes is making enormous progress these days, but until 2008 the discovery of somatic
mutations in the gene encoding isocitrate dehydrogenase-1 , which has been not previously
identified with any known oncogenic pathway, bring great advantages to deeper
understanding of this disease. A better understanding of the functional role of isocitrate
dehydrogenase-1/2 mutations in the pathogenesis of gliomas would propel the development
of more effective treatments. The objective in this review is to highlight these recent
researches that may show promise for histomolecular classification and new treatments for
gliomas.
Data sources
All articles cited in this review were mainly searched from PubMed, which were
published in English from 1996 to 2010.
Study selection
Original articles and critical reviews selected were relevant to the isocitrate
dehydrogenase-1/2 mutation in gliomas and other tumors.
Results
Extraordinary high rates of somatic mutations in isocitrate dehydrogenase-1/2 occur
in the majority of World Health Organization grade II and grade III gliomas as well as grade Ⅳ
secondary glioblastomas. Isocitrate dehydrogenase-1/2 mutations are associated with younger
age at diagnosis and a better prognosis in patients with mutated tumors. The functional role of
isocitrate dehydrogenase-1/2 mutations in the pathogenesis of gliomas is still unclear.
Conclusion
Isocitrate dehydrogenase-1/2 mutations define a specific subtype of gliomas
and may have great significance in the diagnosis, prognosis, and treatment of patients with
these tumors.
G
liomas are the most frequent and lethal tumors of the central nervous system(CNS) and show
wide diversity with location, morphology, genetic status, and response to therapy. These tumors
have been classified as grade I to grade IV based on histopathological and clinical criteria established
by the World Health Organization (WHO).1 Despite intensive therapies, including surgery, radiotherapy,
and chemotherapy, the outcome of glioma patients remains depressing. 2, 3 Current study focused on
identifying genetic alterations implicated in gliomas has become increasingly hot. Then in 2008 by way
of an unbiased, genome-wide analysis of the somatic mutations occurring in 22 human glioblastomas,
researchers found that five of these tumors harbored mutations in the isocitrate dehydrogenase-1 gene
(IDH1), which as a metabolic enzyme gene, had never been implicated in cancer before.4 Subsequently
a genome-wide study declared that mutations that affected amino acid (R132) of IDH1 occurred in
more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in secondary
glioblastomas.5 Tumors without mutations in IDH1 often had mutations affecting the analogous amino
acid (R172) of the IDH2,5 but never affecting IDH3. These results raise numerous questions. What are
the normal functions of the IDH1/2-encoded enzymes? What are the functional consequences of
IDH1/2 mutations in the pathogenesis of gliomas? What is the relationship between IDH1/2 mutation
and clinical diagnosis and treatments? Here we review these new findings.
1
Normal biochemical function of IDH
Xu et al. reported the crystal structure of human IDH1, which, encoded by IDH1 gene on chromosomal
2q33.3, often functioned as homodimers.6 Each homolog comprises a large domain, a clasp domain,
and a small domain. IDH1 homodimers contain two asymmetric active sites, with each active site made
up of a cleft formed by the large and small domains of one IDH1 molecule and the small domain of the
other IDH1 molecule in the dimer. The active sites are exposed to solvent and are accessible to the
substrate and cofactor. The clasp functions to hold the two subunits together to form this active site.
Human IDH1 transforms between an inactive open, an inactive semi-open, and a catalytically active
closed conformation.6 Located atop a β-sheet in the relatively rigid small domain, R132 acts as a
gate-keeper residue and appears to coordinate the hinge movement between the open and closed
conformations. Besides the side chain of R132 residue in the active site of the enzyme, uniquely forms
three hydrogen bonds with the substrate isocitrate but other residues involved in isocitrate binding form
no more than two hydrogen bonds.7
The human genome possess five IDH genes, coding for three distinct IDH enzymes whose coenzymes
are either nicotinamide adenine dinucleotide phosphate(NADP+,IDH1/2) or nicotinamide adenine
dinucleotide(NAD+,IDH3). IDH1 is located in the cytoplasm and peroxisomes, whereas IDH2 and
IDH3 in the mitochondria. IDHs catalyze the oxidative decarboxylation of isocitrate toα-ketoglutarate
(α-KG) and reduce NAD(P)+ to NAD(P)H. IDHs play significant yet distinctive roles in cellular
metabolism, with IDH1 involved in lipid metabolism and glucose sensing, IDH2 in the regulation of
oxidative respiration and IDH3 in aerobic energy production in the tricarboxylic acid (TCA) cycle. In
addition to their roles in normal cellular metabolism, 8-10 they also play a role in the cellular response to
oxidative insults.11, 12 Park and colleagues
13
have confirmed the role of IDH1 and IDH2 as protectors
against various insults.
Frequency and characteristic of IDH1/2 mutation
In order to determine the frequencies and different types of mutations in glioma development, IDH1/2
mutations have been assessed in a large number of gliomas of various types, and the results are striking:
mutations in IDH1 R132 are in fact common(50%–94%)in grades II and III gliomas and secondary
glioblastomas and also occur less frequently in primary glioblastomas(table1).5, 14-20 IDH1 mutaition
were also identified in 3/9(33%)14 and 2/34(6%)21 supratentorial primitive neuroectodermal tumors
(sPNET). Seiz, M., et al. examined the frequency of IDH1 mutations in 35 Gliomatosis cerebri (GC)
samples by direct sequencing and identified IDH1 mutations in 10/24(42%) cases22. In addition,
analysis of the closely related IDH2 has revealed recurrent somatic mutations of IDH2 R172, with most
mutations occurring in tumors lacking IDH1 mutations. 5, 17 Exceptionally one study examined all their
series for both IDH1 and IDH2 mutations and found four anaplastic gliomas with both mutations. 17 The
difference of IDH mutation frequencies in published literatures may partly be attributed to various
numbers of particular subtypes of gliomas; however, the use of different thresholds in scoring weaker
signals as sufficient for a mutation may also play a role. 17
Most recently, IDH1 R132 mutation have also been found in acute myeloid leukemia(AML),23,
B-acute lymphoblastic leukemia,
25
26
colorectal cancer, and prostate carcinoma.
human cancers besides glial tumors were almost absent,
and R140 in AMLs.
24, 28
27
25
24
IDH2 mutations in
except for rare cases of mutations at R172
In the latest study, scientists identified two novel homozygous IDH1 mutations
in thyroid cancer and follicular thyroid cancer.29 There were no IDH1 mutation reported in a broad
2
range of non-CNS tumors,4,
20
or in other CNS tumors including brain metastases of colorectal
30
cancers or melanoma metastases.31
Interestingly, all of the IDH1 mutations identified to date produce a single amino acid substitution at
R132 and all of the IDH2 mutations at R172 except for few cases at R140 in AMLs. 24, 28 In gliomas,
most IDH1 mutations were G395A (R132H) with Amino acid Arg changed to His, whereas IDH2
mutations were G515A(R172K) with Amino acid Arg changed to Lys(table2) 5,
14-20, 32, 33
. IDH1
mutations form the lion’s share of IDH mutations found in cancer, with IDH2 mutation being much less
common. Noticeably, IDH1 mutation of the R132C type was strongly associated with astrocytoma,
while IDH2 mutations predominantly occured in oligodendroglial tumors. 17
Association with other genetic changes(table1)
Tumor protein p53(TP53) encodes the p53 tumor suppressor that regulates cell cycle, apoptosis, DNA
repair and genome stability, and mutations in this pathway often lead to cancer development and poor
outcome.34 TP53 mutations, characteristic of early alterations in the development of an astrocytoma ,
are common in grades II and III astrocytomas and in secondary glioblastomas. In some studies, IDH
mutations have been found to be associated with TP53 mutations,5, 18, 19 although other studies did not
find a statistically significant association.14,
16
1p19q codeltion, which is commonly observed in
oligodendroglial tumors, is frequently observed in IDH-mutated oligodendroglial tumors, 5, 18 and even
in a study ,based on a large series, all tumors with complete 1p19q codeletion(n=128) were found
mutated in the IDH1(n=118) or IDH2(n=10)gene, suggesting that IDH1/2 mutation is a constant feature
in gliomas with complete 1p19q codeletion.33 EGFR amplification are characteristic of higher-grade
tumors,35-37 whereas BRAF fusion gene(at chromosomal band 7q34) is detected as a typical lesion for
PA I.38 O-6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes
alkylating lesions induced by chemotherapeutic agents, and as a result its methylation induces low
expression of MGMT protein resulting in decreasing DNA repair activity and increasing sensitivity to
alkylating agents such as nitrosourea and temozolomide.39, 40 Sanson et al.16 in a series of 404 gliomas
found that the IDH1 mutation was tightly related to the 1p/19q-codeleted group and MGMT
methylation but mutually exclusive with EGFR amplification. IDH1/2 mutations and the BRAF fusion
gene are mutually exclusive ； among IDH1/2-mutated gliomas, 1p/19q codeletion are mutually
exclusive with TP53 mutations and EGFR amplification.41 Besides above-mentioned genetic changes,
IDH1 mutations frequently accompanied alternative lengthening of telomeres (ALT) 42 and existence of
a glioma-CpG island methylator phenotype(G-CIMP). 43
These genetic changes often occur in a staged order during the progression to a high- grade tumor.
Watanabe and colleagues dissected multiple biopsies from the same patients and found that IDH1
mutations always preceded the acquisition of TP53 mutation or 1p/19q codeletion，suggesting that
IDH1 mutations were very early events in gliomagenesis and might affect a common glial precursor
cell population.19 In addition, patients with germline TP53 mutations, which predispose to grade II - IV
astrocytomas, had tumors that harbored somatic IDH1R132C mutations.44
Association with age
Intriguingly, mutations in IDH1/2 predominantly occurred in younger patients except for children.
Parsons, D.W., et al. reported that mutations in IDH1 preferentially occurred in younger GBM patients,
with a mean age of 33 years for IDH1-mutated patients, as opposed to 53 years for patients with
wild-type IDH1(P<0.001).4 Balss, J., et al. reported that In prGBM, AIII and OAIII, the mean age of
3
patients with IDH1 mutations versus patients without was respectively 40.3 years vs 52.6 years, 35.0
years vs 44.4 years, and 44.3years vs 63.5 years.14 Ichimura, K., et al. reported that the mean age of
GBM patients with IDH1 mutations was 41 years, compared with 56 years for GBM patients without
(p =0.002).18 Yan, H., et al. reported that patients with anaplastic astrocytomas or glioblastomas with
IDH1/2 mutations were significantly younger than were patients without (median age,34 years vs.56
years for patients with anaplastic astrocytomas and 32 years vs.59 years for those with glioblastomas;
P<0.001 for both comparisons).5 The association of IDH1 mutations with age seems mostly in the
highly malignant entities，but whether it is true or not will require further studies. However, rare IDH
1/2mutations have been identified in pediatric glioblastomas, and children with IDH1/2-mutated
gliomas are older than the others (median age 16 versus 7 years by De Carli et al. and 17 years vs.5
years by Yan et al.).45, 46
Association with prognosis
To date, only two molecular aberrations have been demonstrated to be of clinical significance in
prospective clinical trials. 1p19q codeltion are associated with a favorable prognosis in patients with
oligodendroglial and oligoastrocytic anaplastic gliomas treated with radiotherapy or radiotherapy plus
chemotherapy.47-50 MGMT promoter hypermethylation is associated with prolonged progression-free
survival (PFS)and overall survival(OS)in patients with glioblastoma treated with alkylating agents such
as nitrosoureas or temozolomide.39,
51-53
High throughput analyses have recently resulted in the
identification of IDH1 mutations as a novel prognostic marker in gliomas.4, 5, 14 Glioma patients with
IDH1/2 mutations survive longer than patients without,4, 5, 18, 54 and multivariate analysis has confirmed
that IDH1 mutation is an independent favorable prognostic marker in GBMs and anaplastic gliomas
after adjustment for other genomic profiles and treatment modality 16, 32, 49 except for the results reported
by Ichimura, K., et al.,18 who indicated that multivariate analysis failed to identify IDH1 status as a
prognostic factor independent of tumor type, grade, or age. Interestingly, those few primary
glioblastomas with IDH1 mutations also have a significantly better prognosis.55, 56
Functional properties in IDH1/2 mutations
Since the discovery of IDH mutations, the functional significance of IDH1/2 mutations in human
cancer remains a mystery. Zhao, S., et al.7 reported that the mutation caused a loss of function of IDH1
and higher levels of hypoxia-inducible factor subunit (HIF-1α) in tumors with mutation than tumors
without, so they concluded that it was a tumor suppressor gene. But Dang, L., et al.57 found high levels
of a single metabolite, 2-hydroxyglutatarate (2-HG), in IDH1-mutated tumors .Their data suggested
that the excess 2-HG which accumulated in vivo contributed to the formation and malignant
progression of gliomas, so later they announced that IDH1 was an oncogene, not a tumor suppressor.
Indeed，while the R132H mutation leads to a loss of enzymatic function for oxidative decarboxylation
of isocitrate, it also results in a gain of enzyme function for the NADPH-dependent reduction of α-KG.
Whether mutant IDH1 is a tumor suppressor gene or oncogene remains unsolved, yet we may discuss
from correlatively IDH-mutated metabolites such as α-KG, NADPH, 2-HG and HIF-1α.
α-KG
IDH1 mutation impairs the enzyme’s affinity for its substrate and dominantly inhibits the normal
function of wild-type IDH1 to convert isocitrate to α-KG through the formation of catalytically inactive
heterodimers, so, as a consequence, α-KG levels were reduced.7 Further study revealed that mutated
IDH1/2 reduce α-KG to D-2-HG while converting NADPH to NADP+.24, 57, 58 Experiments suggested
4
that α-KG levels decreased in cells transfected with mutant IDH1. 7 Xiong’s group also observed a
decrease of α-KG in cells with mutant IDH1.59 But Dang, L., et al. observed that the difference in
average α-KG between mutated-IDH1 tumors and wild-type IDH1 tumors was not statistically
significant, so it was for other proximal TCA cycle metabolites. 57 If α-KG don’t decrease, why would
α-KG levels stay the same since the mutations in IDH1 impair its ability to produce α-KG and the new
enzyme function for the NADPH-dependent reduction of α-KG consume it? The question remains
unsettled.
NADPH
The production of NADPH has been linked to the suppression of apoptosis and to enhanced cell
survival and growth.60-62 NADPH is required for the synthesis of glutathione, which protects cells from
redox stress and promotes resistance to apoptosis. 60 Moreover, cytosolic NADPH is the substrate for
the membrane-associated NADPH oxidases, whose production of hydrogen peroxide inhibits protein
tyrosine phosphatases, thereby promoting sustained activation of kinases that promote cell-autonomous
survival and mitogenic signaling.61 IDH1 and, to a lesser extent, IDH2 provide a significant fraction of
cellular NADPH for these processes.
62
The total NADPH production capacity in glioblastoma was
provided for 65% by IDH activity and the occurrence of R132 IDH1 mutation reduced this capacity by
38%.63 That is to say, IDH1 mutation in glioblastoma hinders NADPH production. In a sense, it is in
accordance with the acquired function converting α-KG, and NADPH into D-2-HG and NADP +.
Although NADPH is required for the synthesis of glutathione, which protects cells from redox stress,
there is still lack of biological data to support the hypothesis that decreased production of NADPH
caused by IDH mutations may impair a survival advantage and even the increase or decrease of
NADPH is controversial. Glial cells may have a higher-than-normal level of α-KG and a high level of
feedback inhibition of their IDH activity. Therefore, mutations that affect end-product inhibition might
facilitate increased production of NADPH in glial cells. 64 The question of NADPH level in
IDH-mutated gliomas awaits further confirmation.
2-HG
The normal metabolic role of 2-HG is not completely understood but 2-HG is not unnatural to cells. It
can be generated by specific α-KG reductase enzymes65 and oxidized back toα-KG by 2-HG
dehydrogenases(2-HGD). The novel enzymatic activity associated with R132 mutations in IDH1
results in the production of 2-HG in gliomas that harbor these mutations and 2-HG is the direct product
of NADPH-dependent α-KG reduction.57 Experiments showed that cancer tissue samples with IDH1/2
mutations had more than 100-fold higher concentrations of 2-HG than cancers without.24, 57, 58 The
accumulating metabolite, 2-HG, exists in the form of two enantiomers, l-2-HG and D-2-HG (each the
mirror image of the other), both of which accumulate whenever the relevant converting enzyme is
defective. D-2-HGD or L-2-HGD for inactivating mutations was analyzed in patients with sporadic
brain tumors without IDH1/2 mutations and there was no evidence for mutations in the genes
D-2-HGD and L-2-HGD as an alternative mechanism for raised 2-HG levels in brain tumors and for
distinct alleles of these genes conferring an increased risk for tumorigenesis.66 The clinical features of
pathological accumulation of 2-HG differ markedly according to the type of enantiomer involved.
Pathological accumulation of the L-2-HG is characterized by progressive neuronal defects and recently
linked to increased risk of brain tumors including gliomas, 67 but the D-2-HG generated by mutant
IDH1 protein(demonstrated by Dang et al.) is not known to have an increased risk for developing brain
tumors.
If 2-HG is associated with cancer initiation and progression, following hypotheses may be acceptable.
5
Elevated brain levels of 2-HG result in increased ROS levels，68, 69 potentially contributing to an
increased risk of cancer. 2-HG may also be toxic to cells by competitively inhibiting glutamate and/or
α-KG utilizing enzymes, such as transaminases which allow utilization of glutamate nitrogen for amino
and nucleic acid biosynthesis, and α-KG-dependent prolyl hydroxylases(PHDs) which regulate HIF-1α
levels.57 2-HG also acts on the family of dioxygenases known as histone demethylases, which regulate
gene expression among other processes by removing methyl groups from histones (proteins around
which DNA is coiled). 2-HG can also act on the tumor microenvironment and disable mitochondria,
thus leading to the reprogramming of the cells and basically pushing the cells toward anerobic
glycolysis(so basically promote the so-called Warburg effect).59 Otto Warburg observed that in most
cancer cells, energy is produced predominantly by aerobic glycolysis in the cytosol, rather than by
oxidation of pyruvate in mitochondria, as in most normal cells. He postulated that this change in
metabolism is the fundamental cause of cancer.70
HIF
HIF, is a master regulator of genes that are activated by low oxygen levels and regulates the expression
of genes implicated in glucose metabolism, angiogenesis, cell motility and invasion, and other
signaling pathways that are critical to tumor growth.71 PHDs use α-KG as a substrate for a reaction that
normally targets HIF-1α for degradation. The loss of activity of two other TCA cycle enzymes
mentioned earlier, succinate dehydrogenase (SDH) or fumarate hydratase (FH), supports
tumorigenesis by increasing succinate or fumarate. These substrates inhibit the PHDs by competing
with their cosubstrate α-KG,72 causing the activation of the HIF transcription factor and high levels of
HIF-1α.73 Experiments showed that HIF-1α levels were higher in human gliomas with IDH1 mutations
than without mutations,7 and high levels of HIF-1α can be transported into the nucleus for
transcriptional activity.64, 71, 74 IDH mutants could lead to lower cellular α-KG levels by consuming this
compound, which may lead to PHDs inactivation. Alternatively, 2-HG produced by IDH mutants has
been thought to competitively inhibit PHDs by occupying the α-KG-binding site on these enzymes.75
However, grades II and III gliomas do not demonstrate angiogenesis, as would be expected for tumors
that activate this hypoxia signaling pathway. 73 Finally, increased expression of HIF-1 target genes is not
found in AMLs,23 which calls into question the idea that HIF-1α stabilization is a major function of the
IDH mutations. Furthermore, it is still be unknown whether the level of α-KG in IDH-mutated tumors
is definitely decreased.
Utility of research and clinical application
IDH mutations seem to play a central role in the pathogenesis of gliomas and define a specific subtype
of gliomas. IDH mutations generally associate with specific gene expression signatures, 76 and
determination of the gene expression environment in mutated and nonmutated tumors of specific tumor
types may shed light on the mechanism of IDH-mutated gliomagenesis. Determining whether IDH
status is an independent prognostic factor for any of the tumor types that contain these mutations may
guide clinical management of a lethal group of cancers. Therefore, the IDH1 status should be
considered in the design of preclinical and clinical studies in future.
Although the IDH-mutated studies are incomplete and still controversial, they are paving the way for
diagnostic and therapeutic application. One study has concluded that combined molecular analysis of
BRAF and IDH1 is a sensitive and highly specific approach to separate pilocytic astrocytoma from
diffuse astrocytoma.38 IDH1 mutation is a strong predictor of a more favorable prognosis and the most
specific biomarker of secondary glioblastomas that complements clinical criteria for distinguishing
6
them from primary glioblastomas.32 This could be useful in cases especially when scant material is
available for histopathological analysis.
The localization of IDH1 /2 mutations to a single amino acid (R132 and R172, respectively)should
simplify the use of this genetic alteration for diagnostic purposes, needless to sequence DNA for
assessing IDH1 status. The current procedure not requiring sequencing but relying on polymerase chain
reaction (PCR) and restriction endonucleases recognizing a site composed of mismatched primer and
IDH1 mutation has recently been adopted widely.77 The real-time PCR/fluorescence melting curve
analysis assay,78 which has been used to evaluate the methylation status of the MGMT gene,79 and
rapid detection based on pyrosequencing 80 provide prompt and sensitive detection of IDH mutations in
formalin-fixed, paraffin-embedded tissues. Two mouse monoclonal antibodies targeting the IDH1
R132H mutation IMab-181 and mIDH1R132H,82 shows high specificity and sensitivity in the detection
of mutations .Especially, mIDH1R132H can differentiate reactive gliosis from neoplastic glial cells in
grade II and III gliomas and allow identifying tumor cells in post-therapy specimens with extensive
reactive changes.83 Measurement of 2-HG production may also simplify the diagnosis and management
of glioma patients, especially if this compound is also elevated in cerebrospinal fluid, serum, or urine
of patients.84
Future direction
Why are IDH genes mutated in the majority of gliomas? What are the cellular consequences of IDH1
mutations in gliomas? Should IDH1 status be used as a stratification factor in clinical trials? What role
does IDH1 play in response to chemotherapy and/or radiotherapy? All these tissues remain unsettled
and the solutions are certain to be relevant for basic and clinical cancer research.
These recent studies have partially shown the relationship of α-KG, NADPH, D- 2-HG, HIF-1α and
mutated IDH1 in gliomas. Long-term research may require the use of mammalian tissue for model. Pet
dogs that develop spontaneous gliomas have been proposed as a model to test human glioma
therapies,85 but now we should pay attention to the genetic differences between human and canine
tumors for studies using this model because IDH1 /2 hotspot mutations are not found in canine
gliomas.86
Further studies are needed to determine whether IDH1 status could influence radiotherapy and
chemotherapy. Dubbink, H.J., et al. reported that presence of IDH1 mutations significantly improved
overall survival but did not affect outcome of temozolomide treatment. 87 In patients with anaplastic
oligodendroglial tumours treated with radiotherapy alone or radiotherapy with adjuvant PCV
(procarbazine, lomustine, and vincristine), the presence of IDH1 mutations had no predictive value for
outcome to PCV.88
It is very likely that in the near future, large-scale genomic expression studies based on IDH mutations
are expected to refine the molecular classification of gliomas to replace the histological classification
and should help establish these mutant genes and the related metabolic pathways as attractive targets
for guiding glioma management. For example, it is vital to take into account the mutant genes present
in each patient’s tumor before chemotherapeutic agents that target molecular pathways can ever be
expected to achieve maximal clinical efficacy. Given the tumor specificity of metabolic enzyme
mutations and the striking difference between the cellular metabolism of cancer and normal cells,
IDH-mutated enzymes as prevalent and specific alterations in gliomas may prove to be fruitful targets
for anticancer therapies.64 Several dozen anticancer agents directly targeting mutant or wild-type IDH
are under development or being tested.59, 89 However, any such improvements in the treatment for
7
patients with IDH-mutated gliomas will hinge on a better understanding of the functional role of the
mutant IDH in the pathogenesis of these tumors.
8
Table1. Frequency of IDH1/2 mutations and other common genetic changes in gliomas
Gliomas*
IDH1 mutation†
(range of percentages)
IDH2 mutation
TP53 mutation
1p19q codeletion
EGFRamp
PA I
1/41,0/21, 0/3,
(0-9.7)
0/3,0/21
0/21
0/38
0/21
(33.3-88.2)
0/9,0/2,2/227
13/25,11/22
6/34,3/22, 0/30
0/17, 0/30
2/30
22/30
1/20,0/9,6/128
3/31,2/34, 8/51
30/50,23/54,26/34
0/11, 0/51
0/38,3/31
A II
34/46,3/9 10/12
165/227,13/22,
60/68, 25/30
O II
36/51,16/20,6/9
(66.6-82.0)
41/54,105/128,
2/51
31/51
23/34,31/39,41/51
OA II
36/46,1/1,26/34,
(50.0-100)
0/1,1/76
6/26,8/20, 1/3
24/45,2/34,1/20
0/10,0/3
(44.4-77.8)
0/9,1/21,2/228
13/30,42/62
5/43,3/62, 5/52
1/22,1/52
2/52
34/52
0/9,9/174, 3/36
4/31,3/20, 4/36
35/53,19/49,12/20
0/4, 0/36
62/76,10/20,16/17
3/3
A III
29/47,4/9,12/21
9/18,146/228,
32/62,21/27,36/52
O III
36/54,8/9,24/49
(49.0-88.9)
121/174,12/20
30/36
6/8,31/36
OA III
29/37, 3/4,34/54
(63.0-100)
0/4,11/177
6/22,11/23, 5/7
117/177,18/23
26/36,6/54,6/23
0/8
3/7
10/14, 7/7
prGBM
7/99,11/183,6/173
(3.5-7.1)
0/123
15/88,59/173
3/59,6/123,11/94
secGBM
7/8,10/13,5/10
6/73,3/173, 5/123
26/71, 47/123
28/123
(50.0-87.5)
0/13
7/8,6/10,8/13
1/8,0/10
0/8,0/13
0/15
2/3,5/15
0/3
0/2
28/34,11/13,11/15
pedGBM
1/14,0/15
*PA I: Pilocytic astrocytoma WHO grade I, A II: Diffuse astrocytoma WHO grade II, O II: Oligodendroglioma WHO grade II, OA II:
Oligoastrocytoma WHO grade II, A III: Anaplastic astrocytoma WHO grade III, O III: Anaplastic oligodendroglioma WHO grade III, OA
III: Anaplastic oligoastrocytoma WHO grade III, prGBM: Primary Glioblastoma WHO grade IV, secGBM: Secondary glioblastoma
WHO grade IV, pedGBM: Pediatric Glioblastoma WHO grade IV
†Number of mutated sample/total number of samples of neuropathological type analyzed for each report of the special type.
9
Table2. different reports of IDH1/2 mutation types
Amino acid substitution
Different reports
Percentage(%) in total IDH1 mutation
R132H
R132C
R132S
R132L
R132G
Balss, J., et al.
92.7
3.6
1.8
0.5
0.9
Horbinski, C., et al.
78.4
2.7
5.4
2.7
2.7
Nobusawa, S., et al.
83
2.8
2.8
Sanson, M., et al.
89
3.2
1.9
1.3
4.5
Hartmann, C., et al.
92.7
4.2
1.5
0.2
1.4
Ichimura, K., et al.
92.4
3.4
0.8
3.4
Watanabe, T., et al.
91
4.6
0.8
3.8
Yan, H., et al.
88.2
4.3
2.5
4.3
0.6
Bleeker, F.E., et al.
73.9
13.0
4.3
4.3
4.3
Labussiere, M., et al.
88.6
3.8
1.6
1.6
4.4
Number in total IDH2 mutation
R172G
R172K
R172M
R172W
2.7
11.1
2/9
20/31
6/31
4/9
3/9
12/16
1/16
5/31
1/16
R132H: Amino acid change Arg→His with Nucleotide change G395A(CGT→CAT) ; R132C: Amino acid change Arg→Cys with Nucleotide change
C394T(CGT→TGT); R132S: Amino acid change Arg→Ser with Nucleotide change C394A(CGT→AGT); R132L: Amino acid change Arg→Leu with
Nucleotide change G395T(CGT→CTT); R132G: Amino acid change Arg→Gly with Nucleotide change C394G(CGT→GGT); R172G : Amino acid change
Arg→Gly with Nucleotide change A514G(AGG→GGG) R172K: Amino acid change Arg→Lys with Nucleotide change G515A(AGG→AAG); R172M:
Amino acid change Arg→Met with Nucleotide change G515T(AGG→ATG); R172W: Amino acid change Arg→Try with Nucleotide change
A514T(AGG→TGG).
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