MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic Oligodendrogliomas and Oligoastrocytomas. A report from EORTC study 26951.
OBJECTIVE
The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others.


METHODS
We conducted genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted the CpG island hypermethylated phenotype (CIMP) and MGMT promoter methylation (MGMT-STP27) status.


RESULTS
We first show that methylation profiling can be conducted on archival tissues with a performance that is similar to snap-frozen tissue samples. We then conducted methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP+ or MGMT-STP27 methylated tumors had an improved survival compared with CIMP- and/or MGMT-STP27 unmethylated tumors [median overall survival (OS), 1.05 vs. 6.46 years and 1.06 vs. 3.8 years, both P < 0.0001 for CIMP and MGMT-STP27 status, respectively]. Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex, performance score, and review diagnosis in the model. CIMP+ and MGMT-STP27 methylated tumors showed a clear benefit from adjuvant PCV chemotherapy: the median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.51 years, respectively (P = 0.0033); for MGMT-STP27 methylated samples, it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P = 0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response.


CONCLUSIONS
MGMT-STP27 may be used to guide treatment decisions in this tumor type.
Authors' Affiliations: Departments of Neurology, Biostatistics, and Pathology, Neuro-Oncology Unit Erasmus MC, Rotterdam; AP-HP, Groupe Hospitalier Pitie Salpêtrière, Service de Neurologie 2 Mazarin and Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), Paris, France; Department of Pathology, UMCU, Utrecht; Department of Pathology, UMCG, Groningen; Department of Neurology, St. Elisabeth Hospital, Tilburg; Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen; Department of Pathology, Free University Medical Center, Amsterdam, the Netherlands; and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium.
Martin J
MJ
van den Bent
Lale
L
Erdem-Eraslan
Ahmed
A
Idbaih
Johan
J
de Rooi
Paul H C
PH
Eilers
Wim G M
WG
Spliet
Wilfred F A
WF
den Dunnen
Cees
C
Tijssen
Pieter
P
Wesseling
Peter A E
PA
Sillevis Smitt
Johan M
JM
Kros
Thierry
T
Gorlia
Pim J
PJ
French
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008130:Lomustine / Q000008:administration & dosage; D008297:Male; D009837:Oligodendroglioma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D010641:Phenotype; D011344:Procarbazine / Q000008:administration & dosage; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014750:Vincristine / Q000008:administration & dosage
D015415:Biomarkers; D025521:Tumor Suppressor Proteins; D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes