IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group.
OBJECTIVE
Recent studies have shown the prognostic significance of IDH1 mutations in glioma. It is yet unclear if IDH1 mutations are predictive for outcome to chemotherapy. We determined the effect of IDH1 mutations on progression-free survival and overall survival (OS), and its correlation with other clinical and molecular features in the prospective randomized European Organization for Research and Treatment of Cancer study 26951 on adjuvant procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) in anaplastic oligodendroglioma.


METHODS
IDH1 and IDH2 alterations of the mutational hotspot codons R132 and R172 were assessed by the bidirectional cycle sequencing of PCR-amplified fragments. MGMT promoter methylation was assessed using methylation-specific multiplex ligation-dependant probe amplification based on methylation-sensitive restriction analysis. Loss of chromosomes 1p, 19q, 10, and 10q and the gain of 7 and the EGFR gene were assessed with fluorescence in situ hybridization.


RESULTS
From 159 patients, sufficient material was available for IDH1 analysis. In 151 and 118 of these patients, respectively, the 1p/19q status and the MGMT promoter methylation status were known. In 73 cases (46%), an IDH1 mutation was found and only one IDH2 mutation was identified. The presence of IDH1 mutations correlated with 1p/19q codeletion and MGMT promoter methylation, and inversely correlated with loss of chromosome 10, EGFR amplification, polysomy of chromosome 7, and the presence of necrosis. IDH1 mutations were found to be prognostic in the radiotherapy- and the radiotherapy/PCV-treated patients, for both progression-free survival and OS. With Cox proportional hazard modeling for OS with stepwise selection, IDH1 mutations and 1p/19q codeletion but not MGMT promoter methylation were independent prognostic factors.


CONCLUSIONS
In this homogeneously treated group of anaplastic oligodendroglioma patients, the presence of IDH1 mutations was found to carry a very strong prognostic significance for OS but without evidence of a predictive significance for outcome to PCV chemotherapy. IDH1 mutations were strongly associated with 1p/19q codeletion and MGMT promoter methylation.
Dept Neuro-Oncology and Pathology, Daniel den Hoed Cancer Center and Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands. m.vandenbent@erasmusmc.nl
Martin J
MJ
van den Bent
Hendrikus J
HJ
Dubbink
Yannick
Y
Marie
Alba A
AA
Brandes
Martin J B
MJ
Taphoorn
Pieter
P
Wesseling
Marc
M
Frenay
Cees C
CC
Tijssen
Denis
D
Lacombe
Ahmed
A
Idbaih
Ronald
R
van Marion
Johan M
JM
Kros
Winand N M
WN
Dinjens
Thierry
T
Gorlia
Marc
M
Sanson
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D003131:Combined Modality Therapy; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D018773:Genes, erbB-1; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008130:Lomustine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009837:Oligodendroglioma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D016133:Polymerase Chain Reaction; D011344:Procarbazine / Q000627:therapeutic use; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011878:Radiotherapy; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
D025521:Tumor Suppressor Proteins; D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes