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

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Abstract

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.

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Acknowledgements

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.

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    Authors and Affiliations

    1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

      Timothy E. Richardson, Dwight Oliver, Jack M. Raisanen, Chunyu Cai & Kimmo J. Hatanpaa

    2. Department of Pathology, New York University Langone Medical Center, New York City, NY, 10016, USA

      Matija Snuderl, Jonathan Serrano, Matthias A. Karajannis & Adriana Heguy

    3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

      Elizabeth A. Maher

    4. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

      Elizabeth A. Maher, Edward Pan, Amyn A. Habib & Robert M. Bachoo

    5. Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

      Edward Pan & Samuel Barnett

    6. North Texas Veterans Affairs Medical Center, Dallas, TX, 75216, USA

      Amyn A. Habib

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    1. Timothy E. Richardson
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    Timothy E. Richardson and Matija Snuderl have contributed equally to this work.

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    11060_2017_2431_MOESM1_ESM.jpg

    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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    Richardson, T.E., Snuderl, M., Serrano, J. et al. Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis. J Neurooncol 133, 183–192 (2017). https://doi.org/10.1007/s11060-017-2431-y

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