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Loss of Nuclear p27 Expression and Its Prognostic Role in Relation to Cyclin E and p53 Mutation in Gastroenteropancreatic Neuroendocrine Tumors

Authors' Affiliations: ¹ Medizinische Klinik I, Gastroenterologie/Infektiologie/Rheumatologie and ² Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin; ³ Abteilung für Hämatologie und Onkologie, Charité-Campus Virchow, Berlin, Germany; ⁴ Innere Medizin, Abteilung für Gastroenterologie und Endokrinologie, Philipps Universität Marburg, Germany; and ⁵ Abteilung Innere Medizin II, Universität Freiburg, Freiburg, Germany

Requests for reprints: Patricia Grabowski, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Hindenburgdamm 30, 12200 Berlin, Germany. Phone: 49-30-8445-4579; Fax: 49-30-8445-4481; E-mail: patricia.grabowski{at}charite.de.

Purpose: Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are classified by the WHO, yet its prognostic value needs to be confirmed. Therefore, we aimed to determine the prognostic role of cell cycle key regulatory genes p53, p27^kip1 (p27), and cyclin E in this tumor entity.

Experimental Design: Tumor specimen from 89 patients with a complete follow-up were studied immunohistochemically for p27 and cyclin E expression and for p53 mutations. The functional relevance of p27 was evaluated in the neuroendocrine cell lines BON1 (human) and INS1 (rat) by the use of small interfering RNA.

Results: Twenty-six of 29 benign, well-differentiated endocrine tumors (WHO class 1) showed a high expression (>50%) of p27, whereas all 10 poorly differentiated endocrine carcinomas (WHO class 3) displayed a low expression of p27. Metastatic well-differentiated endocrine carcinomas (WHO class 2) showed a low p27 expression in 20 of 50 (40%) patients, which conferred a poor prognosis (median survival, 57 versus 140 months; P = 0.037). This prognostic dichotomy was improved by the use of a combination of p27 and cyclin E (high cyclin E/low p27 versus low cyclin E/high p27: median survival 53 months versus not reached; P = 0.0044). p53 mutations were rare (1 of 10 poorly differentiated endocrine carcinomas).

Conclusions: Loss of p27 and overexpression of cyclin E play a critical role in the aggressiveness of gastroenteropancreatic neuroendocrine tumors. This coincides with increased cell cycle progression. We propose a discussion whether to incorporate the immunohistochemical expression of p27 into a revised classification to individualize therapeutic strategies in this tumor entity.