Expression of p16INK4A in gastrointestinal stromal tumours (GISTs): two different forms exist that independently correlate with poor prognosis

  1. Florian Haller1,
  2. Abbas Agaimy2,
  3. Silke Cameron3,
  4. Manori Beyer1,
  5. Bastian Gunawan1,
  6. Nicole Happel4,
  7. Claus Langer5,
  8. Giuliano Ramadori3,
  9. Anja Von Heydebreck6,
  10. László Füzesi1

Article first published online: 22 FEB 2010

DOI: 10.1111/j.1365-2559.2010.03478.x

Issue

Histopathology

Histopathology

Volume 56, Issue 3, pages 305–318, February 2010

Additional Information

How to Cite

Haller, F., Agaimy, A., Cameron, S., Beyer, M., Gunawan, B., Happel, N., Langer, C., Ramadori, G., Von Heydebreck, A. and Füzesi, L. (2010), Expression of p16INK4A in gastrointestinal stromal tumours (GISTs): two different forms exist that independently correlate with poor prognosis. Histopathology, 56: 305–318. doi: 10.1111/j.1365-2559.2010.03478.x

Author Information

  1. 1

    Department of Pathology, Georg August University, Göttingen

  2. 2

    Institute of Pathology, Friedrich Alexander University, Erlangen

  3. 3

    Department of Gastroenterology and Endocrinology

  4. 4

    Institute for Biochemistry and Molecular Cell Biology

  5. 5

    Department of General and Visceral Surgery, Georg August University, Göttingen

  6. 6

    Department of Bio- and Chemoinformatics, Merck KGaA, Darmstadt, Germany

*Dr. med. F. Haller, Department of Pathology, University of Göttingen, Robert-Koch-Str. 40, D-37099 Göttingen, Germany. e-mail: florian.haller@med.uni-goettingen.de*Present address: Institute of Pathology, Albert Ludwigs University, Freiburg, Germany.

Publication History

  1. Issue published online: 22 FEB 2010
  2. Article first published online: 22 FEB 2010
  3. Date of submission 29 January 2009 Accepted for publication 21 May 2009

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Keywords:

  • E2F1;
  • GIST;
  • p16INK4A;
  • prognosis

Haller F, Agaimy A, Cameron S, Beyer M, Gunawan B, Happel N, Langer C, Ramadori G, von Heydebreck A & Füzesi L (2010) Histopathology56, 305–318

Expression of p16INK4Ain gastrointestinal stromal tumours (GISTs): two different forms exist that independently correlate with poor prognosis

Aims:  To determine the prognostic impact of p16INK4A expression in gastrointestinal stromal tumours (GISTs), which is currently being questioned, with both loss and overexpression said to be correlated with poor prognosis.

Methods and results:  Two different forms of p16INK4A were identified, presenting with predominantly nuclear and cytoplasmic expression pattern, respectively. The immunohistochemical expression of the two forms and their correlation with E2F1 and prognosis were analysed in a series of 120 GISTs with clinical follow-up. Low nuclear p16INK4A expression correlated with E2F1 up-regulation, higher mitotic counts, and tumour progression. The prognostic value of nuclear p16INK4A expression was only marginally significant (P = 0.05). Strong expression of the cytoplasmic p16INK4A form was significantly associated with shorter disease-free survival (P = 2 × 10−5). The prognostic impact of strong expression of the cytoplasmic p16INK4A form was independent of anatomical localization, tumour size and mitotic counts, and significant even among the cohort of tumours with high malignant potential.

Conclusions:  Low expression of the nuclear p16INK4A form and strong expression of the cytoplasmic p16INK4A form both represent two independent parameters each associated with tumour progression in GISTs. Low nuclear p16INK4A expression enables E2F1 up-regulation and consecutive accelerated cell proliferation. In contrast, strong cytoplasmic p16INK4A expression probably reflects a negative feedback loop as a result of (as yet unknown) oncogenic events.

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