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


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=2x10(-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.
Haller
Florian
F
Department of Pathology, Georg August University, Göttingen, Germany. florian.haller@med.uni-goettingen.de
Agaimy
Abbas
A
Cameron
Silke
S
Beyer
Manori
M
Gunawan
Bastian
B
Happel
Nicole
N
Langer
Claus
C
Ramadori
Giuliano
G
von Heydebreck
Anja
A
Füzesi
László
L
D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D050687:E2F1 Transcription Factor / Q000096:biosynthesis; D004591:Electrophoresis, Polyacrylamide Gel; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D020033:Protein Isoforms