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High proliferation index, as determined by immunohistochemical expression of Aurora kinase B and geminin, indicates poor prognosis in neuroblastomas

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Abstract

Expression profile analysis of cell cycle biomarkers provides a powerful index of the proliferative state of tumors, which is linked to disease aggressiveness. We investigated the impact of the biomarkers of S-G2-M phases of cell cycle, Aurora kinase B (AURKB) and geminin (GMNN), on disease progression in neuroblastomas. The expression of AURKB and GMNN was studied by immunostaining 84 neuroblastomas. A proliferation index (PI) was obtained on scanned immunostained slides using image analysis software. The median PI was 8.5 % for AURKB- and 16.8 % for GMNN-stained slides with a high correlation between the two (r s  = 0.72, P < 0.001). The PI for both markers was significantly higher in neuroblastomas from patients with unfavorable clinical (high-risk group, advanced stage, age ≥18 months at presentation, primary abdominal compared to extra-abdominal sites), biological (MYCN amplification, 1p deletion, 17q gain), and pathological (undifferentiated or poorly differentiated status, high mitosis-karyorrhexis index, [MKI], unfavorable histology) factors. Using Cox regression models, a higher-than-median AURKB and GMNN PI was associated with a significantly shorter overall survival (OS) and event-free survival (EFS) in univariable analysis. In multivariable analysis, a high AURKB PI was associated with significantly shorter OS and EFS, independent of MYCN amplification, and significantly shorter EFS, independent of MKI. High GMNN PI was also associated with significantly shorter OS and EFS after adjusting for MYCN amplification but failed to reach statistical significance after adjusting for MKI. Our study shows that in neuroblastomas, AURKB- or GMNN-based PI provides valuable prognostic information and high PI indicates aggressive disease.

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Acknowledgments

The authors acknowledge the clinicians, radiologists, and all the individuals who were involved in the management of the patients, and thank Above & Beyond Charities for their support.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. School of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK

    Pramila Ramani

  2. Department of Histopathology, Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, BS2 8HW, UK

    Pramila Ramani & Emile Sowa-Avugrah

  3. School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK

    Margaret T. May

Authors
  1. Pramila Ramani
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  2. Emile Sowa-Avugrah
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  3. Margaret T. May
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Correspondence to Pramila Ramani.

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Ramani, P., Sowa-Avugrah, E. & May, M.T. High proliferation index, as determined by immunohistochemical expression of Aurora kinase B and geminin, indicates poor prognosis in neuroblastomas. Virchows Arch 467, 319–327 (2015). https://doi.org/10.1007/s00428-015-1806-8

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  • DOI: https://doi.org/10.1007/s00428-015-1806-8

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