title: Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations.
abstract: OBJECTIVE
  The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival.
  
  
  METHODS
  We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques.
  
  
  RESULTS
  The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment.
  
  
  CONCLUSIONS
  IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.
authors.affiliation: Authors' Affiliations: Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover; Department of Neuropathology, and German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neuropathology, University Hospital of Heidelberg, Institute for Pathology, Heidelberg; Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig; Departments of Neurosurgery and Neuropathology, University of Bonn, Bonn; Department of Neurosurgery, University of Hamburg, Hamburg; Department of Neurosurgery, University of Dresden, Dresden; Department of Neurosurgery, University of Munich, Munich; Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany; and Department of Neurology, University Hospital Zurich, and Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Bettina
authors.initials: B
authors.lastname: Hentschel
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Tonn
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D005909:Glioblastoma / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D017741:Survivors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D045643:DNA Repair Enzymes