Expression of p16INK4A in gastrointestinal stromal tumours (GISTs): two different forms exist that independently correlate with poor prognosis
Article first published online: 22 FEB 2010
© 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Limited
Volume 56, Issue 3, pages 305–318, February 2010
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
- Issue published online: 22 FEB 2010
- Article first published online: 22 FEB 2010
- Date of submission 29 January 2009 Accepted for publication 21 May 2009
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.