Expression of p16(INK4A) in gastrointestinal stromal tumours (GISTs): two different forms exist that independently correlate with poor prognosis

Abstract

Aims: To determine the prognostic impact of p16(INK4A) 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 p16(INK4A) 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 p16(INK4A) expression correlated with E2F1 up-regulation, higher mitotic counts, and tumour progression. The prognostic value of nuclear p16(INK4A) expression was only marginally significant (P = 0.05). Strong expression of the cytoplasmic p16(INK4A) form was significantly associated with shorter disease-free survival (P = 2 x 10) 5). The prognostic impact of strong expression of the cytoplasmic p16(INK4A) 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 p16(INK4A) form and strong expression of the cytoplasmic p16(INK4A) form both represent two independent parameters each associated with tumour progression in GISTs. Low nuclear p16(INK4A) expression enables E2F1 up-regulation and consecutive accelerated cell proliferation. In contrast, strong cytoplasmic p16(INK4A) expression probably reflects a negative feedback loop as a result of (as yet unknown) oncogenic events.