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Molecular sub-group-specific immunophenotypic changes are associated with outcome in recurrent posterior fossa ependymoma

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Abstract

Better understanding of ependymoma (EPN) biology at relapse is needed to improve therapy at this critical event. Convincing data exist defining transcriptionally distinct posterior fossa (PF) sub-groups A and B at diagnosis. The clinical and biological consequence of these sub-groups at recurrence has not yet been defined. Genome and transcriptome microarray profiles and clinical variables of matched primary and first recurrent PF EPN pairs were used to identify biologically distinct patterns of progression between EPN sub-groups at recurrence. Key findings were validated by histology and immune function assays. Transcriptomic profiles were partially conserved at recurrence. However, 4 of 14 paired samples changed sub-groups at recurrence, and significant sub-group-specific transcriptomic changes between primary and recurrent tumors were identified, which were predominantly immune-related. Further examination revealed that Group A primary tumors harbor an immune gene signature and cellular functionality consistent with an immunosuppressive phenotype associated with tissue remodeling and wound healing. Conversely, Group B tumors develop an adaptive, antigen-specific immune response signature and increased T-cell infiltration at recurrence. Clinical distinctions between sub-groups become more apparent after first recurrence. Group A tumors were more often sub-totally resected and had a significantly shorter time to subsequent progression and worse overall survival. Minimal tumor-specific genomic changes were observed for either PF Groups A or B at recurrence. Molecular sub-groups of PF EPN convey distinct immunobiologic signatures at diagnosis and recurrence, providing potential biologic rationale to their disparate clinical outcomes. Immunotherapeutic approaches may be warranted, particularly in Group A PF EPN.

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Acknowledgments

This work was supported by the National Institutes of Health (R01 CA140614), Ruth L. Kirschstein National Research Service Award (T32 CA082086-13), the Tanner Seebaum Foundation, and the Cancer League of Colorado, Inc.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pediatrics, University of Colorado Denver, 12800 East 19th Avenue, Aurora, CO, 80045, USA

    Lindsey M. Hoffman, Andrew M. Donson, Andrea M. Griesinger, Vladimir Amani, Molly S. Hemenway, Michael Wang & Nicholas K. Foreman

  2. Department of Pulmonary and Critical Care Medicine, University of Colorado Denver, 12800 East 19th Avenue, Aurora, CO, 80045, USA

    Ichiro Nakachi

  3. Department of Radiation Oncology, University of Colorado Denver, 12800 East 19th Avenue, Aurora, CO, 80045, USA

    Arthur K. Liu

  4. Department of Neurosurgery, University of Colorado Denver, 12800 East 19th Avenue, Aurora, CO, 80045, USA

    Diane K. Birks, Todd C. Hankinson & Michael H. Handler

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  1. Lindsey M. Hoffman
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  9. Michael Wang
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  12. Nicholas K. Foreman
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Correspondence to Lindsey M. Hoffman.

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Hoffman, L.M., Donson, A.M., Nakachi, I. et al. Molecular sub-group-specific immunophenotypic changes are associated with outcome in recurrent posterior fossa ependymoma. Acta Neuropathol 127, 731–745 (2014). https://doi.org/10.1007/s00401-013-1212-8

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  • DOI: https://doi.org/10.1007/s00401-013-1212-8

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