# IDH Mutations: Genotype-Phenotype Correlation and Prognostic Impact

Authors: Xiao-Wei Wang; Pietro Ciccarino; Marta Rossetto; Blandine Boisselier; Yannick Marie; Virginie Desestret; Vincent Gleize; Karima Mokhtari; Marc Sanson; Marianne Labussière
Journal: BioMed Research International
 (2014)

---

## Abstract

IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1R132H, IDH1nonR132H, and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1nonR132H in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated—which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.


---

## Body

## 1. Introduction

The WHO Classification of Tumors of the Central Nervous System is the universal standard for classifying and grading brain neoplasms [1]. According to the presumed cell of origin, gliomas have been classified into three major groups: astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. Based on the presence or absence of malignant features: cell density, nuclear atypia, mitosis, microvascular proliferation, and necrosis, the WHO classification distinguishes grades I, II (LGG), III (anaplastic), and IV (glioblastomas, GBM) [2]. However, this classification suffers from a lack of reproducibility, with a high interobserver variability, often leading to discordant results between centers [3–5].In these settings, there is a need for the identification of additional prognostic markers to refine the WHO classification in order to define more homogeneous subgroups. Mutations in theIDH1 (isocitrate dehydrogenase 1) gene have been first reported in 2008 [6]. Since then, theIDH1 mutation has been recognized as the most frequent alterations in gliomas, occurring in 40% of glial tumors [7–9] and is the most powerful prognostic factor ever described in gliomas [10, 11]. Less frequently the mitochondrial isoformIDH2 is mutated.We have investigated the mutational status ofIDH1 andIDH2 in a cohort of 1305 glioma patients and correlated it with the genomic profile and the outcome.


## 2. Patients and Methods

### 2.1. Patients and Tissue Samples

Patients were selected retrospectively according to the following criteria: histologic diagnosis of grade II to grade IV glioma; clinical data and follow-up available in the neurooncology database; and written informed consent. The inclusion period extends from May 1987 to October 2010. Tumor DNA was extracted from both frozen and paraffin embedded formalin fixed tumors, when available, using the QIAmp DNA minikit, as described by the manufacturer (Qiagen). CGH-array analysis, LOH (loss of heterozygosity) analysis,EGFR amplification, andP16 deletion assessment were performed as previously described [12].


### 2.2. Determination ofIDH1 andIDH2 Mutational Status

The genomic regions spanning wild-type R132 ofIDH1 and wild-type R172 ofIDH2 were analyzed by direct sequencing using the following primers: IDH1f 5-AGAAGAGGGTTGAGGAGTTCAA, IDH1r 5-CACATACAAGTTGGAAATTTCTGG, IDH2f 5-AGCCCATCATCTGCAAAAAC, and IDH2r 5-CTAGGCGAGGAGCTCCAGT, as previously described [10]. Forward and reverse chains were analyzed on an ABI prism 3730 DNA analyzer (Perkin Elmer).IDH2 mutational status was determined by Sanger sequencing and by PCR HRM. The latter approach allowing only the detection of anIDH2 mutation presence, we have only the type of base substitution for 15 tumors. HRM was performed as previously described [13].


### 2.3.MGMT Status andTP53 Mutations Determination

DNA methylation status of theMGMT promoter was determined by bisulfite modification and subsequent nested MSP, a two-stage PCR approach, as previously described [14].TP53 gene mutations were screened for exons 5–8 by using previously reported primers and methods [15].


### 2.4. Statistical Analysis

Theχ
2 test (or Fisher’s exact test when one subgroup was <5) was used to compare the genotype distribution. The association with continuous variables was calculated with a Mann-Whitney test.Overall survival (OS) was defined as the time between the diagnosis and death or last follow-up. Patients who were still alive at last follow-up were considered as a censored event in analysis. Progression free survival (PFS) was defined as the time between the diagnosis and recurrence or last follow-up. Patients who were recurrence-free at last follow-up were considered as a censored event in analysis. To find clinical and/or genomic factors related to OS (or PFS), survival curves were calculated according to the Kaplan-Meier method and differences between curves were assessed using the log-rank test. Variables with a significantP value were used to build multivariate Cox model.


## 2.1. Patients and Tissue Samples

Patients were selected retrospectively according to the following criteria: histologic diagnosis of grade II to grade IV glioma; clinical data and follow-up available in the neurooncology database; and written informed consent. The inclusion period extends from May 1987 to October 2010. Tumor DNA was extracted from both frozen and paraffin embedded formalin fixed tumors, when available, using the QIAmp DNA minikit, as described by the manufacturer (Qiagen). CGH-array analysis, LOH (loss of heterozygosity) analysis,EGFR amplification, andP16 deletion assessment were performed as previously described [12].


## 2.2. Determination ofIDH1 andIDH2 Mutational Status

The genomic regions spanning wild-type R132 ofIDH1 and wild-type R172 ofIDH2 were analyzed by direct sequencing using the following primers: IDH1f 5-AGAAGAGGGTTGAGGAGTTCAA, IDH1r 5-CACATACAAGTTGGAAATTTCTGG, IDH2f 5-AGCCCATCATCTGCAAAAAC, and IDH2r 5-CTAGGCGAGGAGCTCCAGT, as previously described [10]. Forward and reverse chains were analyzed on an ABI prism 3730 DNA analyzer (Perkin Elmer).IDH2 mutational status was determined by Sanger sequencing and by PCR HRM. The latter approach allowing only the detection of anIDH2 mutation presence, we have only the type of base substitution for 15 tumors. HRM was performed as previously described [13].


## 2.3.MGMT Status andTP53 Mutations Determination

DNA methylation status of theMGMT promoter was determined by bisulfite modification and subsequent nested MSP, a two-stage PCR approach, as previously described [14].TP53 gene mutations were screened for exons 5–8 by using previously reported primers and methods [15].


## 2.4. Statistical Analysis

Theχ
2 test (or Fisher’s exact test when one subgroup was <5) was used to compare the genotype distribution. The association with continuous variables was calculated with a Mann-Whitney test.Overall survival (OS) was defined as the time between the diagnosis and death or last follow-up. Patients who were still alive at last follow-up were considered as a censored event in analysis. Progression free survival (PFS) was defined as the time between the diagnosis and recurrence or last follow-up. Patients who were recurrence-free at last follow-up were considered as a censored event in analysis. To find clinical and/or genomic factors related to OS (or PFS), survival curves were calculated according to the Kaplan-Meier method and differences between curves were assessed using the log-rank test. Variables with a significantP value were used to build multivariate Cox model.


## 3.  Results

We have screened for the presence of codon-132 mutations in theIDH1 gene in a large cohort of 1305 gliomas, including 436 WHO grade II, 394 WHO grade III, and 475 WHO grade IV gliomas. The presence ofIDH2 mutation was investigated in a cohort of 980 gliomas (379 grade II, 289 grade III, 312 grade IV). In the whole cohort, sex ratio was 1.3 and median age at diagnosis was 49.2 years (range, 16.1 to 89.1 years). The characteristics of the population are indicated in Table 1.Table 1
Patients demographics and clinical characteristics.
Glioma by grade
Characteristics
II(n
=
436)
III(n
=
394)
IV(n
=
475)
Age, years
Median
38.1
47.8
58.5
Range
16.1–77.0
19.1–89.1
18.2–89.1
KPS
Median
90
90
80
Range
50–100
60–100
40–100
Biopsy (%)
25.6
28.7
26.6
Tumor removal (%)
74.4
71.3
73.4
Overall survival, months
Median
121.9
41.7
14.5
Range
0.1–238.9
0.1–249.3
0.1–89.1
Progression free survival, months
Median
38.8
19.5
8.2
Range
0.1–189.7
0.1–249.3
0.1–80.5
KPS: Karnofsky performance score; PFS: progression-free survival.Taken together we found 609/1305IDH1 and 30/980IDH2 mutations (global mutation rates of 46.7% and 3.1%, resp.). No tumor harbored bothIDH1 andIDH2 mutations (Supplementary Table 1 available online at http://dx.doi.org/10.1155/2014/540236). Patients with IDH1 mutations were younger for the whole series (median age 40.6 years for IDH1 mutated patients versus 55.9 years; P
<
0.0001) and also for grades III and IV separately (median age at diagnosis 44.4 and 47.8 years for grades III and IVIDH mutated tumors, versus 51.5 and 59.0 years for grades III and IV nonmutated gliomas; P
=
0.0012 and P
<
0.0001, resp.).


### 3.1. Genotype-Phenotype Correlations

IDH1 mutations affected 72.5% (316/436) grade II, 63.7% (251/394) grade III, and 8.8% (42/475) grade IV gliomas. We looked then for association between glioma subtypes (astrocytic, mixed, and oligodendroglial tumors) andIDH1
R132H,IDH1
nonR132H mutations, andIDH2 mutations. In grades II and III gliomas,IDH2 mutations were overrepresented in oligodendrogliomas (22 IDH2 mutations out of 330IDH mutated tumors; 6.7%), compared to astrocytomas (1/60; 1.7%) and mixed gliomas (6/176; 3.4%) (P
=
0.049). In contrast, we found thatIDH1
nonR132H mutations were more frequent in astrocytic (6/60, 10.0%IDH mutated tumors) and mixed tumors (15/176, 8.5%), compared to oligodendroglial tumors (15/332, 4.5%, P
=
0.037).


### 3.2.IDH Mutations Are Associated with Tumor Genomic Profile

We have then evaluated the association ofIDH mutation with the molecular alterations commonly found in gliomas (Table 2). We found thatIDH mutations were significantly associated withMGMT promoter methylation (P
<
0.0001). In contrast, there was a strong association between the absence ofIDH mutation and complete loss of chromosome 10q,EGFR amplification andP16 deletion (P
<
0.0001 in each case).Table 2
Comparison of histologic distribution, molecular alterations, and prognostic impact betweenIDH mutated and wild type patients.
n
IDH1 mutated tumors*
IDH2 mutated tumors
IDHwild type tumors
Histologic subtypes
Astrocytic tumors
448
87
2
359
AII
61
43  (2)
1
17
AIII
33
17  (4)
0
16
GBM
354
27  (1)
1
326
Oligodendroglial tumors
584
347
22
215
OII
243
182  (10)
15
46
OIII
220
150  (5)
7
63
GBMO
121
15  (1)
0
106
Mixed tumors
275
176
6
93
OAII
134
92  (6)
5
37
OAIII
141
84  (9)
1
56
Molecular alterations
MGMT promoter methylation
587
195/256  (76.2%)
172/331  (52.0%)
EGFR amplification
1248
9/609  (1.5%)
196/639  (30.7%)
Complete 10q loss
1148
57/572  (10.0%)
359/576  (62.3%)
P16 deletion
1232
63/595  (10.6%)
203/637  (31.8%)
TP53 mutation
396
64/178  (35.9%)
49/218  (22.5%)
Prognostic impact
Overall survival
Grade II
309
136.5
67.0a
Grade III
303
136.9
20.1b
Grade IV
435
26.6
14.2c
Progression free survival
Grade II
309
41.3
28.5d
Grade III
303
31.9
10.4e
Grade IV
435
10.0
8.1f
*For histologic subtypes, the number in parentheses indicates the number of I
D
H
1
n
o
n
R
132
H mutations. a,b,e
P
<
0.0001; c
P
=
0.0004; d
P
=
0.0363; f
P
=
0.0008.Complete 1p19q codeletion was found in 150 gliomas: theIDH1 gene was mutated in 137 cases (91.3%) and theIDH2 gene was mutated in 12 of the 13 remaining tumors. Taken together, theIDH genes were altered in 99.3% (149/150) of the 1p19q codeleted tumors.TP53 mutation was analyzed by Sanger sequencing in 396 tumors: 64/178 (35.9%)IDH mutated tumors were also mutated onTP53, versus 49/218 (22.5%) of the nonmutated tumors (P
=
0.0036).TP53 mutation was correlated with astrocytic histology: 95 tumors out of 286 (33.2%) astrocytic and mixed gliomas wereTP53 mutated, whereas only 16.4% (18/110) of oligodendrogliomas were mutated onTP53 (P
=
0.0008).TP53 mutation was rarely associated with 1p19q codeletion: 1p19q codeleted gliomas were less frequentlyP53 mutated (4/52, 7.7%), as compared to the noncodeleted tumors (103/170, 60.6%; P
<
0.0001). When excluding 1p19q codeleted tumors (considered as the hallmark of oligodendrogliomas),TP53 mutation was even more strongly correlated with IDH mutation: 57/98 (58.2%) ofIDH mutated tumors was also mutated onTP53, versus 46/175 (26.2%, P
<
0.0001) in nonmutated gliomas.


### 3.3.IDH1 Mutation Is an Independent Prognostic Factor of Good Outcome

We investigated the prognostic impact ofIDH status in grade II, grade III, and grade IV gliomas. For each grade,IDH mutated patients have significantly longer overall survival and progression free survival thanIDH normal patients (Figure 1 and Table 2).Prognostic impact ofIDH status on overall survival (a) and progression free survival (b) in grade II to IV gliomas.
(a)
(b)We then entered the following factors as candidate variables in the multivariate Cox proportional hazards regression model analysis:IDH mutation,P16 deletion, 1p19q codeletion, extent of surgery, Karnofsky index, and age at diagnosis (Table 3).IDH mutation was a strong and independent predictor of a better outcome (hazard ratio for overall survival= 0.358; 95% CI, 0.248 to 0.517; P
<
0.0001).Table 3
Multivariate Cox proportional hazards regression model analysis of survival of the 1305 glioma patients cohort.MGMT promoter methylation was not included in this analysis due to a low number of evaluable patients for this parameter.
Parameter
Overall survival
Progression free survival
HR
95% CI for HR
P
HR
95% CI for HR
P
Age > 60 years
1.831
1.358 to 2.467
0.0001
1.479
1.158 to 1.889
0.0018
Surgery extent
0.775
0.588 to 1.021
0.0715
1.045
0.823 to 1.326
0.7199
1p19q codeletion
0.202
0.098 to 0.415
<0.0001
0.491
0.326 to 0.739
0.0007
IDH mutation
0.358
0.248 to 0.517
<0.0001
0.467
0.348 to 0.627
<0.0001
IK > 70
0.419
0.315 to 0.556
<0.0001
0.489
0.375 to 0.636
<0.0001
P16 deletion
1.513
1.168 to 1.960
0.0018
1.471
1.165 to 1.858
0.0013Moreover, as previously described [16], we stratified the grade II and grade III tumors according to 1p19q codeletion andIDH status, thus defining three prognostic groups: 1p19q codeleted (andIDH mutated),IDH mutated, and others (Figure 2).Overall survival (OS, (a)) and progression free survival (PFS, (b)) for grade II and III gliomas patients stratified according to 1p19q codeletion and presence of IDH mutations. Median OS were 150.9, 69.0, and 25.4 months for 1p19q/IDH mutated, IDH mutated, and other groups, respectively. Median PFS were 51.1, 34.3, and 12.2 months for 1p19q/IDH mutated, IDH mutated, and other groups, respectively.
(a)
(b)Whatever the grade, patients harboring the 1p19q codeletion have a significantly longer survival (median OS: 150.9 months) than patients only harboringIDH mutation (69.0 months) or none of these alterations (25.4 months). We looked then atTP53 mutation in these three prognostic groups and foundP53 mutation strongly associated with group 2 in both grades II and III (Table 4). For example in grade II gliomas,TP53 was mutated in 58.5% in group 2, versus 8.8% and 27.8% in groups 1 and 3, respectively (P
<
0.0001 and P
=
0.031, resp.).Table 4
Association ofTP53 mutation with 1p19q codeleted tumors and IDH mutated tumors.
TP53
Mutated
Normal
Percentage
Difference toIDH mutated group (P)
Grade II
1p19q/IDH mutated
3
31
8.8%
<0.0001
IDH mutated
31
22
58.5%
—
others
5
13
27.8%
0.0309
Grade III
1p19q/IDH mutated
1
16
6.3%
0.0002
IDH mutated
21
13
61.8%
—
others
11
24
31.4%
0.0160


## 3.1. Genotype-Phenotype Correlations

IDH1 mutations affected 72.5% (316/436) grade II, 63.7% (251/394) grade III, and 8.8% (42/475) grade IV gliomas. We looked then for association between glioma subtypes (astrocytic, mixed, and oligodendroglial tumors) andIDH1
R132H,IDH1
nonR132H mutations, andIDH2 mutations. In grades II and III gliomas,IDH2 mutations were overrepresented in oligodendrogliomas (22 IDH2 mutations out of 330IDH mutated tumors; 6.7%), compared to astrocytomas (1/60; 1.7%) and mixed gliomas (6/176; 3.4%) (P
=
0.049). In contrast, we found thatIDH1
nonR132H mutations were more frequent in astrocytic (6/60, 10.0%IDH mutated tumors) and mixed tumors (15/176, 8.5%), compared to oligodendroglial tumors (15/332, 4.5%, P
=
0.037).


## 3.2.IDH Mutations Are Associated with Tumor Genomic Profile

We have then evaluated the association ofIDH mutation with the molecular alterations commonly found in gliomas (Table 2). We found thatIDH mutations were significantly associated withMGMT promoter methylation (P
<
0.0001). In contrast, there was a strong association between the absence ofIDH mutation and complete loss of chromosome 10q,EGFR amplification andP16 deletion (P
<
0.0001 in each case).Table 2
Comparison of histologic distribution, molecular alterations, and prognostic impact betweenIDH mutated and wild type patients.
n
IDH1 mutated tumors*
IDH2 mutated tumors
IDHwild type tumors
Histologic subtypes
Astrocytic tumors
448
87
2
359
AII
61
43  (2)
1
17
AIII
33
17  (4)
0
16
GBM
354
27  (1)
1
326
Oligodendroglial tumors
584
347
22
215
OII
243
182  (10)
15
46
OIII
220
150  (5)
7
63
GBMO
121
15  (1)
0
106
Mixed tumors
275
176
6
93
OAII
134
92  (6)
5
37
OAIII
141
84  (9)
1
56
Molecular alterations
MGMT promoter methylation
587
195/256  (76.2%)
172/331  (52.0%)
EGFR amplification
1248
9/609  (1.5%)
196/639  (30.7%)
Complete 10q loss
1148
57/572  (10.0%)
359/576  (62.3%)
P16 deletion
1232
63/595  (10.6%)
203/637  (31.8%)
TP53 mutation
396
64/178  (35.9%)
49/218  (22.5%)
Prognostic impact
Overall survival
Grade II
309
136.5
67.0a
Grade III
303
136.9
20.1b
Grade IV
435
26.6
14.2c
Progression free survival
Grade II
309
41.3
28.5d
Grade III
303
31.9
10.4e
Grade IV
435
10.0
8.1f
*For histologic subtypes, the number in parentheses indicates the number of I
D
H
1
n
o
n
R
132
H mutations. a,b,e
P
<
0.0001; c
P
=
0.0004; d
P
=
0.0363; f
P
=
0.0008.Complete 1p19q codeletion was found in 150 gliomas: theIDH1 gene was mutated in 137 cases (91.3%) and theIDH2 gene was mutated in 12 of the 13 remaining tumors. Taken together, theIDH genes were altered in 99.3% (149/150) of the 1p19q codeleted tumors.TP53 mutation was analyzed by Sanger sequencing in 396 tumors: 64/178 (35.9%)IDH mutated tumors were also mutated onTP53, versus 49/218 (22.5%) of the nonmutated tumors (P
=
0.0036).TP53 mutation was correlated with astrocytic histology: 95 tumors out of 286 (33.2%) astrocytic and mixed gliomas wereTP53 mutated, whereas only 16.4% (18/110) of oligodendrogliomas were mutated onTP53 (P
=
0.0008).TP53 mutation was rarely associated with 1p19q codeletion: 1p19q codeleted gliomas were less frequentlyP53 mutated (4/52, 7.7%), as compared to the noncodeleted tumors (103/170, 60.6%; P
<
0.0001). When excluding 1p19q codeleted tumors (considered as the hallmark of oligodendrogliomas),TP53 mutation was even more strongly correlated with IDH mutation: 57/98 (58.2%) ofIDH mutated tumors was also mutated onTP53, versus 46/175 (26.2%, P
<
0.0001) in nonmutated gliomas.


## 3.3.IDH1 Mutation Is an Independent Prognostic Factor of Good Outcome

We investigated the prognostic impact ofIDH status in grade II, grade III, and grade IV gliomas. For each grade,IDH mutated patients have significantly longer overall survival and progression free survival thanIDH normal patients (Figure 1 and Table 2).Prognostic impact ofIDH status on overall survival (a) and progression free survival (b) in grade II to IV gliomas.
(a)
(b)We then entered the following factors as candidate variables in the multivariate Cox proportional hazards regression model analysis:IDH mutation,P16 deletion, 1p19q codeletion, extent of surgery, Karnofsky index, and age at diagnosis (Table 3).IDH mutation was a strong and independent predictor of a better outcome (hazard ratio for overall survival= 0.358; 95% CI, 0.248 to 0.517; P
<
0.0001).Table 3
Multivariate Cox proportional hazards regression model analysis of survival of the 1305 glioma patients cohort.MGMT promoter methylation was not included in this analysis due to a low number of evaluable patients for this parameter.
Parameter
Overall survival
Progression free survival
HR
95% CI for HR
P
HR
95% CI for HR
P
Age > 60 years
1.831
1.358 to 2.467
0.0001
1.479
1.158 to 1.889
0.0018
Surgery extent
0.775
0.588 to 1.021
0.0715
1.045
0.823 to 1.326
0.7199
1p19q codeletion
0.202
0.098 to 0.415
<0.0001
0.491
0.326 to 0.739
0.0007
IDH mutation
0.358
0.248 to 0.517
<0.0001
0.467
0.348 to 0.627
<0.0001
IK > 70
0.419
0.315 to 0.556
<0.0001
0.489
0.375 to 0.636
<0.0001
P16 deletion
1.513
1.168 to 1.960
0.0018
1.471
1.165 to 1.858
0.0013Moreover, as previously described [16], we stratified the grade II and grade III tumors according to 1p19q codeletion andIDH status, thus defining three prognostic groups: 1p19q codeleted (andIDH mutated),IDH mutated, and others (Figure 2).Overall survival (OS, (a)) and progression free survival (PFS, (b)) for grade II and III gliomas patients stratified according to 1p19q codeletion and presence of IDH mutations. Median OS were 150.9, 69.0, and 25.4 months for 1p19q/IDH mutated, IDH mutated, and other groups, respectively. Median PFS were 51.1, 34.3, and 12.2 months for 1p19q/IDH mutated, IDH mutated, and other groups, respectively.
(a)
(b)Whatever the grade, patients harboring the 1p19q codeletion have a significantly longer survival (median OS: 150.9 months) than patients only harboringIDH mutation (69.0 months) or none of these alterations (25.4 months). We looked then atTP53 mutation in these three prognostic groups and foundP53 mutation strongly associated with group 2 in both grades II and III (Table 4). For example in grade II gliomas,TP53 was mutated in 58.5% in group 2, versus 8.8% and 27.8% in groups 1 and 3, respectively (P
<
0.0001 and P
=
0.031, resp.).Table 4
Association ofTP53 mutation with 1p19q codeleted tumors and IDH mutated tumors.
TP53
Mutated
Normal
Percentage
Difference toIDH mutated group (P)
Grade II
1p19q/IDH mutated
3
31
8.8%
<0.0001
IDH mutated
31
22
58.5%
—
others
5
13
27.8%
0.0309
Grade III
1p19q/IDH mutated
1
16
6.3%
0.0002
IDH mutated
21
13
61.8%
—
others
11
24
31.4%
0.0160


## 4. Discussion

In this large series, we investigated the place ofIDH1/IDH2 mutation in gliomas, in particular in different genotypes and phenotypes. As a first result, we confirmed the strong association ofIDH mutations with the tumor genomic profile [10]: virtually all 1p19q codeleted tumors areIDH mutated [17, 18] whereasIDH mutation is extremely rare in gliomas withEGFR amplification. Secondly, we showed that the type of mutation is related to the molecular profile. TheIDH1
R132H mutation represents 90% of allIDH mutations. However, we found here thatIDH1
nonR132H mutations are associated with astrocytic tumors [19], whereasIDH2 mutations are associated with oligodendrogliomas. The 1p19q codeletion is a hallmark of oligodendroglial phenotype and we found similar results when tumors are stratified according to histological subtype.The association ofIDH mutation withTP53 mutation has been widely studied in literature and has led to contradictory results.IDH mutation was found associated withTP53 mutation in several studies [11, 18, 20–24] but other authors did not find such an association [10, 25]. We found an association betweenIDH andTP53 mutations, but we showedTP53 mutation correlated with astrocytic phenotype, in contrast withIDH mutation more associated with the oligodendroglial phenotype. Therefore, when excluding 1p19q codeleted tumors, mostly oligodendroglial, and rarelyTP53 mutated, we found a stronger positive association betweenIDH andTP53 mutations. This result is concordant with the data of Gravendeel et al. who found a correlation betweenTP53 mutation and I
D
H
1
n
o
n
R
132
H mutation [26].Confirming previous data obtained on smaller cohorts [10, 16], our findings showed that gliomas patients harboring anIDH1 mutated tumor present an improved outcome, compared to patients with anIDH1 normal tumor. The multivariate analysis shows thatIDH status is an independent prognostic factor in a 1332 glioma patients cohort. To further explore the prognostic impact ofIDH1 mutation, we subdivided both grade II and III gliomas patients in three prognostic subgroups, based on the 1p19q codeletion andIDH1 mutation status ((i)IDH mut/1p19qdel, (ii)IDH mut/1p19qnon del, (iii)IDH non mut/1p19qnon del.). In line with a recent study [22], we found thatTP53 mutation characterizes the group 2 (IDH mut non 1p19q codeleted). The third group with the worst prognosis contains mainly triple negative gliomas (non 1p19q codeleted, nonIDH mutated, nonTP53 mutated) [22].Taken together, our results show thatIDH mutation combined with other genomic marker can be used to refine the prognostic classification of gliomas, independently of tumor grade. With the recent results of randomized trial,IDH1 mutation has become, with 1p19q codeletion, a predictive marker of the response to chemotherapy [27–29].



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*Source: 540236-2014-04-30.xml*