Journal of Neuro-Oncology

, Volume 133, Issue 1, pp 183–192 | Cite as

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis

  • Timothy E. Richardson
  • Matija Snuderl
  • Jonathan Serrano
  • Matthias A. Karajannis
  • Adriana Heguy
  • Dwight Oliver
  • Jack M. Raisanen
  • Elizabeth A. Maher
  • Edward Pan
  • Samuel Barnett
  • Chunyu Cai
  • Amyn A. Habib
  • Robert M. Bachoo
  • Kimmo J. HatanpaaEmail author
Clinical Study


According to the recently updated World Health Organization (WHO) classification (2016), grade II–III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II–III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II–III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II–III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.


Astrocytoma Glioblastoma Rapidly progressing astrocytoma IDH mutation Methylation array 



The authors would like to thank Niccole Williams and Agatha Villegas for administrative professional services. We also thank Ping Shang for some of the immunohistochemical stains. The authors would like to thank Stefan Pfister, David T. W. Jones, Martin Sill and Volker Hovestadt for their help with optimization of the 450 k Illumina Infinium methylation profiling for copy number analysis. A.A.H. was supported, in part, by a grant from the Department of Veteran’s Affairs (I01BX002559). The study was supported by the Friedberg Charitable Foundation grant to M.S. and M.A.K.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

11060_2017_2431_MOESM1_ESM.jpg (828 kb)
Supplemental Figure 1. Copy number analysis derived from the Illumina Infinium Human Methylation 450k array data, showing four conventional, indolent IDH-mutated astrocytomas with no subsequent progression. These four tumors show relatively little copy number changes across all chromosomes compared with the four tumors in our study group. (JPG 827 KB)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Timothy E. Richardson
    • 1
  • Matija Snuderl
    • 2
  • Jonathan Serrano
    • 2
  • Matthias A. Karajannis
    • 2
  • Adriana Heguy
    • 2
  • Dwight Oliver
    • 1
  • Jack M. Raisanen
    • 1
  • Elizabeth A. Maher
    • 3
    • 4
  • Edward Pan
    • 4
    • 5
  • Samuel Barnett
    • 5
  • Chunyu Cai
    • 1
  • Amyn A. Habib
    • 4
    • 6
  • Robert M. Bachoo
    • 4
  • Kimmo J. Hatanpaa
    • 1
    Email author
  1. 1.Department of PathologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of PathologyNew York University Langone Medical CenterNew York CityUSA
  3. 3.Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasUSA
  4. 4.Department of Neurology and NeurotherapeuticsUniversity of Texas Southwestern Medical CenterDallasUSA
  5. 5.Department of Neurological SurgeryUniversity of Texas Southwestern Medical CenterDallasUSA
  6. 6.North Texas Veterans Affairs Medical CenterDallasUSA

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