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A prognostic gene expression signature in infratentorial ependymoma

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Abstract

Patients with ependymoma exhibit a wide range of clinical outcomes that are currently unexplained by clinical or histological factors. Little is known regarding molecular biomarkers that could predict clinical behavior. Since recent data suggest that these tumors display biological characteristics according to their location (cerebral vs. infratentorial vs. spinal cord), rather than explore a broad spectrum of ependymoma, we focused on molecular alterations in ependymomas arising in the infratentorial compartment. Unsupervised clustering of available gene expression microarray data revealed two major subgroups of infratentorial ependymoma. Group 1 tumors over expressed genes that were associated with mesenchyme, Group 2 tumors showed no distinct gene ontologies. To assess the prognostic significance of these gene expression subgroups, real-time reverse transcriptase polymerase chain reaction assays were performed on genes defining the subgroups in a training set. This resulted in a 10-gene prognostic signature. Multivariate analysis showed that the 10-gene signature was an independent predictor of recurrence-free survival after adjusting for clinical factors. Evaluation of an external dataset describing subgroups of infratentorial ependymomas showed concordance of subgroup definition, including validation of the mesenchymal subclass. Importantly, the 10-gene signature was validated as a predictor of recurrence-free survival in this dataset. Taken together, the results indicate a link between clinical outcome and biologically identified subsets of infratentorial ependymoma and offer the potential for prognostic testing to estimate clinical aggressiveness in these tumors.

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Acknowledgments

We thank the following individuals for their efforts in support of this work. From MD Anderson Cancer Center: Susan Cweren and Mary Jo Reyes; from the University of Pittsburgh Medical Center: Frank Lieberman, Ronald Hamilton, Regina Jakacki, Stephanie Bortoluzzi and Angela Krol; from the Children’s National Medical Center: Amulya Rao, and Ashley Hill; from the University of California, San Francisco: Ashley DeSilva; from St Jude Children’s Research Hospital: Letitia Williams and Annemarie McClellan; from Children’s Memorial Hospital: Kelly Verel and Nicole Reinholdt; from Cincinnati Children’s Hospital: Christine Minges, Lori Davis and Rebecca Turner; from Henry Ford Hospital: Lisa Scarpace; from Memorial Sloan Kettering Cancer Centre: Joseph Parks and Meredith Gondo; from University San Giovanni Battista Torino-Italy: Polly Graziani and Chiara Bosa. This work was supported by the Collaborative Ependymoma Research Network (CERN) Foundation and a SPORE in Brain Cancer grant from the NIH (5 P50 CA127001-03).

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Authors and Affiliations

  1. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Khalida Wani, Aditya Raghunathan, Alicia Ledoux, Charmaine Wilson, Lihong Long & Ken Aldape

  2. Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA

    David Ellison

  3. Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Richard Gilbertson

  4. Department of Neuro-Oncology, Children’s Memorial Hospital, Chicago, IL, USA

    Stewart Goldman

  5. Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Children’s National Medical Center for Neuroscience Research (CNR), Washington, DC, USA

    Roger J. Packer

  6. Department of Neuro-Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Maryam Fouladi

  7. Department of Neurological Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ian Pollack

  8. Department of Neurosurgery, Henry Ford West Bloomfield Hospital, West Bloomfield, MI, USA

    Tom Mikkelsen

  9. Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, USA

    Michael Prados

  10. Department of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Antonio Omuro

  11. Department of Neuro-Oncology, Medical School, University of Torino, Turin, Italy

    Riccardo Soffietti

  12. Department of Neurosurgery, Methodist Neurological Institute, Houston, TX, USA

    Brian Vaillant

  13. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Terri S. Armstrong, Elizabeth Vera-Bolanos & Mark R. Gilbert

  14. Department of Family Health, The University of Texas Health Science Centre School of Nursing, Houston, TX, USA

    Terri S. Armstrong

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  1. Khalida Wani
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Correspondence to Ken Aldape.

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Supplementary Tables 1 (DOCX 46 kb)

401_2012_941_MOESM2_ESM.tif

Supplementary Fig. 1 Overall experimental approach for the study. The number of microarray samples from each site is indicated. INDT: Instituto Nazionale Dei Tumori; UCD: University of Colorado at Denver; SJCRH: St. Jude Children’s Research Hospital; VCU: Virginia Commonwealth University. (TIFF 282 kb)

401_2012_941_MOESM3_ESM.tif

Supplementary Fig. 2 Comparison of the transcriptomal Groups 1 and 2 with the Johnson et al posterior fossa subgroups G, H and I. Group 1 tumors are similar to subgroup H and I tumors in their gene expression profile while group 2 tumors resemble subgroup G. (TIFF 673 kb)

401_2012_941_MOESM4_ESM.tif

Supplementary Fig. 3 Expression of TOP2A and its correlation with metagene score and patient survival. a) Immunohistochemical staining for TOP2A showing a negative and positive case. b) Box-whisker plot showing the association of TOP2A staining and metagene score. High TOP2A immunostaining score corresponded with a low metagene score (unfavorable response group) while low TOP2A immunostaining was seen in the high metagene score group (favorable group).The Fisher’s exact test, two-tailed, was used for statistical significance calculation. c-d) Kaplan-Meier survival curves showing a worse progression-free and overall survival in the group of cases that had high levels of TOP2A protein expression as detected by immunohistochemistry. (TIFF 5918 kb)

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Wani, K., Armstrong, T.S., Vera-Bolanos, E. et al. A prognostic gene expression signature in infratentorial ependymoma. Acta Neuropathol 123, 727–738 (2012). https://doi.org/10.1007/s00401-012-0941-4

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