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High expression of Polycomb group protein EZH2 predicts poor survival in salivary gland adenoid cystic carcinoma
  1. Hedy Vekony (h.vekony{at}vumc.nl)
  1. Academic Centre for Dentistry (ACTA), VU University Medical Center (VUmc), Amsterdam, Netherlands
    1. Frank M Raaphorst (frank.raaphorst{at}biofarmind.nl)
    1. Biofarmind, The Hague, Netherlands
      1. Arie P Otte (arieotte{at}science.uva.nl)
      1. Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
        1. Maarten Van Lohuizen (m.v.lohuizen{at}nki.nl)
        1. Netherlands Cancer Institute, Amsterdam, Netherlands
          1. C. Rene Leemans (cr.leemans{at}vumc.nl)
          1. VU University Medical Center (VUmc), Amsterdam, Netherlands
            1. Isaac Van der Waal (i.vanderwaal{at}vumc.nl)
            1. Academic Centre for Dentistry (ACTA), VU University Medical Center (VUmc), Amsterdam, Netherlands
              1. Elisabeth Bloemena (e.bloemena{at}vumc.nl)
              1. Academic Centre for Dentistry (ACTA), VU University Medical Center, Netherlands

                Abstract

                Background: Prognosis of adenoid cystic carcinoma (ACC), a malignant salivary gland tumor, depends on clinicopathological parameters. To decipher ACC’s biological behavior and to identify patients at risk of developing metastases, additional markers are needed.

                Methods: We investigated immunohistochemically the expression of the cell cycle proteins p53, Cyclin D1, p16INK4a, E2F1 and Ki-67, together with the Polycomb group (PcG) proteins BMI-1, MEL-18, EZH2, and EED in 21 formalin-fixed, paraffin-embedded primary ACCs in relation to tumor characteristics.

                Results: ACC reveals significantly increased expression of the cell cycle proteins compared to normal salivary tissue (n=17). Members of the two PcG complexes display mutually exclusive expression in normal salivary gland tissue, with BMI-1 and MEL-18 being abundantly present. In ACC, this expression pattern is disturbed, with EZH2 and EED showing significantly increased expression levels. In univariate analysis, presence of recurrence, poor differentiation, and high EZH2 levels (>25% immunopositivity) significantly correlate with unfavorable outcome. ACCs with high proliferative rate (>25% Ki-67 immunopositivity) significantly correlate with high levels of EZH2 and p16. Only the development of recurrence was an independent prognostic factor of survival in multivariate analysis.

                Conclusions: Expression of PcG complexes and of essential cell cycle proteins is highly deregulated in ACC. Also, EZH2 expression has prognostic relevance in this malignancy.

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