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Acta Neuropathol Commun. 2019 Jun 5;7(1):89. doi: 10.1186/s40478-019-0745-z.

Predictive MGMT status in a homogeneous cohort of IDH wildtype glioblastoma patients.

Author information

1
Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1 (Virchowweg 15), 10117, Berlin, Germany. josefine.radke@charite.de.
2
German Cancer Consortium (DKTK), Heidelberg, Germany, Partner Site Charité Berlin, Berlin, Germany. josefine.radke@charite.de.
3
Berlin Institute of Health (BIH), 10178, Berlin, Germany. josefine.radke@charite.de.
4
Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1 (Virchowweg 15), 10117, Berlin, Germany.
5
German Cancer Consortium (DKTK), Heidelberg, Germany, Partner Site Charité Berlin, Berlin, Germany.
6
Berlin Institute of Health (BIH), 10178, Berlin, Germany.
7
Department of Neurosurgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
8
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometrics and Clinical Epidemiology, Berlin, Germany.
9
Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117, Berlin, Germany.
10
German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117, Berlin, Germany.
11
Department of Neurosurgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany. julia.onken@charite.de.
12
BSIO Berlin School of Integrative Oncology, University Medicine Charité, 13353, Berlin, Germany. julia.onken@charite.de.

Abstract

Methylation of the O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter is predictive for treatment response in glioblastoma patients. However, precise predictive cutoff values to distinguish "MGMT methylated" from "MGMT unmethylated" patients remain highly debated in terms of pyrosequencing (PSQ) analysis. We retrospectively analyzed a clinically and molecularly very well-characterized cohort of 111 IDH wildtype glioblastoma patients, who underwent gross total tumor resection and received standard Stupp treatment. Detailed clinical parameters were obtained. Predictive cutoff values for MGMT promoter methylation were determined using ROC curve analysis and survival curve comparison using Log-rank (Mantel-Cox) test. MGMT status was analyzed using pyrosequencing (PSQ), semi-quantitative methylation specific PCR (sqMSP) and direct bisulfite sequencing (dBiSeq). Highly methylated (> 20%) MGMT correlated with significantly improved progression-free survival (PFS) and overall survival (OS) in our cohort. Median PFS was 7.2 months in the unmethylated group (UM, < 10% mean methylation), 10.4 months in the low methylated group (LM, 10-20% mean methylation) and 19.83 months in the highly methylated group (HM, > 20% mean methylation). Median OS was 13.4 months for UM, 17.9 months for LM and 29.93 months for HM. Within the LM group, correlation of PSQ and sqMSP or dBiSeq was only conclusive in 51.5% of our cases. ROC curve analysis revealed superior test precision for survival if additional sqMSP results were considered (AUC = 0.76) compared to PSQ (cutoff 10%) alone (AUC = 0.67). We therefore challenge the widely used, strict PSQ cutoff at 10% which might not fully reflect the clinical response to alkylating agents and suggest applying a second method for MGMT testing (e.g. MSP) to confirm PSQ results for patients with LM MGMT levels if therapeutically relevant.

KEYWORDS:

Glioblastoma; IDH (isocitrate dehydrogenase); Methylation specific PCR (MSP); O(6)-Methylguanine-DNA methyltransferase (MGMT); Pyrosequencing (PSQ); Temozolomide (TMZ)

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