Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations

Clin Cancer Res. 2013 Sep 15;19(18):5146-57. doi: 10.1158/1078-0432.CCR-13-0017. Epub 2013 Aug 5.

Abstract

Purpose: 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.

Experimental design: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / therapy
  • Cohort Studies
  • Combined Modality Therapy
  • DNA Methylation
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • DNA, Neoplasm / genetics
  • ErbB Receptors / genetics
  • Female
  • Follow-Up Studies
  • Gene Amplification
  • Glioblastoma / genetics
  • Glioblastoma / mortality*
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Staging
  • Polymerase Chain Reaction
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • Survival Rate
  • Survivors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics
  • Young Adult

Substances

  • DNA, Neoplasm
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human
  • DNA Modification Methylases
  • MGMT protein, human
  • EGFR protein, human
  • ErbB Receptors
  • DNA Repair Enzymes