DGKI methylation status modulates the prognostic value of MGMT in glioblastoma patients treated with combined radio-chemotherapy with temozolomide

• Published in: PloS one Vol. 9; no. 9; p. e104455
• Main Authors: Etcheverry, Amandine, Aubry, Marc, Idbaih, Ahmed, Vauleon, Elodie, Marie, Yannick, Menei, Philippe, Boniface, Rachel, Figarella-Branger, Dominique, Karayan-Tapon, Lucie, Quillien, Veronique, Sanson, Marc, de Tayrac, Marie, Delattre, Jean-Yves, Mosser, Jean
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18-09-2014; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating - therapeutic use; Biology and life sciences; Brain cancer; Care and treatment; Chemoradiotherapy; Chemotherapy; Cohort Studies; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; Deoxyribonucleic acid; Diacylglycerol Kinase - genetics; Disease-Free Survival; DNA; DNA methylation; DNA Methylation - genetics; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; Female; Gene expression; Genetics; Genomes; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - mortality; Glioblastoma - radiotherapy; Glioblastomas; Humans; Isocitrate Dehydrogenase - genetics; Life Sciences; Male; Medical prognosis; Medicine and Health Sciences; Methylation; Middle Aged; Motivation; Mutation; Neurons and Cognition; Nomograms; Patients; Physical Sciences; Prognosis; Promoter Regions, Genetic - genetics; Proportional Hazards Models; Radiation therapy; Recruitment; Retrospective Studies; Risk groups; Surgery; Survival; Temozolomide; Tumor Suppressor Proteins - genetics; Tumors; Young Adult; France
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0104455

Consistently reported prognostic factors for glioblastoma (GBM) are age, extent of surgery, performance status, IDH1 mutational status, and MGMT promoter methylation status. We aimed to integrate biological and clinical prognostic factors into a nomogram intended to predict the survival time of an individual GBM patient treated with a standard regimen. In a previous study we showed that the methylation status of the DGKI promoter identified patients with MGMT-methylated tumors that responded poorly to the standard regimen. We further evaluated the potential prognostic value of DGKI methylation status.
399 patients with newly diagnosed GBM and treated with a standard regimen were retrospectively included in this study. Survival modelling was performed on two patient populations: intention-to-treat population of all included patients (population 1) and MGMT-methylated patients (population 2). Cox proportional hazard models were fitted to identify the main prognostic factors. A nomogram was developed for population 1. The prognostic value of DGKI promoter methylation status was evaluated on population 1 and population 2.
The nomogram-based stratification of the cohort identified two risk groups (high/low) with significantly different median survival. We validated the prognostic value of DGKI methylation status for MGMT-methylated patients. We also demonstrated that the DGKI methylation status identified 22% of poorly responding patients in the low-risk group defined by the nomogram.
Our results improve the conventional MGMT stratification of GBM patients receiving standard treatment. These results could help the interpretation of published or ongoing clinical trial outcomes and refine patient recruitment in the future.