title: DGKI methylation status modulates the prognostic value of MGMT in glioblastoma patients treated with combined radio-chemotherapy with temozolomide.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France; Centre Hospitalier Universitaire de Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Etcheverry
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France; Plate-forme Génomique Santé Biogenouest, Biosit, Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Aubry
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service de Neurologie 2 Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, INSERM UMRS 975/CNRS UMR 7225/Université Pierre-et-Marie-Curie, Institut du Cerveau et de la Moelle Épinière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France; Département de Biologie Médicale, Centre Eugène Marquis, Rennes, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Vauleon
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service de Neurologie 2 Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.affiliation: Centre Hospitalier Universitaire d'Angers, Service de Neurochirurgie, Angers, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Menei
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Boniface
authors.affiliation: Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire de la Timone, Service d'Anatomie Pathologie et de Neuropathologie, Université Aix-Marseille, Marseille, France; INSERM U911, Université Aix-Marseille, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: INSERM U935, Poitiers, France; Université de Poitiers, Poitiers, France; Centre Hospitalier Universitaire de Poitiers, Laboratoire de Cancérologie Biologique, Poitiers, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Karayan-Tapon
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France; Département de Biologie Médicale, Centre Eugène Marquis, Rennes, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Quillien
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service de Neurologie 2 Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, INSERM UMRS 975/CNRS UMR 7225/Université Pierre-et-Marie-Curie, Institut du Cerveau et de la Moelle Épinière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France; Centre Hospitalier Universitaire de Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: de Tayrac
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service de Neurologie 2 Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, INSERM UMRS 975/CNRS UMR 7225/Université Pierre-et-Marie-Curie, Institut du Cerveau et de la Moelle Épinière, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Delattre
authors.affiliation: CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France; Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France; Plate-forme Génomique Santé Biogenouest, Biosit, Rennes, France; Centre Hospitalier Universitaire de Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Mosser
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D059248:Chemoradiotherapy; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019852:Diacylglycerol Kinase / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000532:radiotherapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D049451:Nomograms; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019852:Diacylglycerol Kinase; D045643:DNA Repair Enzymes; D000077204:Temozolomide