title: Expression of p16INK4A in gastrointestinal stromal tumours (GISTs): two different forms exist that independently correlate with poor prognosis.
abstract: 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.
authors.affiliation: Department of Pathology, Georg August University, Göttingen, Germany. florian.haller@med.uni-goettingen.de
authors.forename: Florian
authors.initials: F
authors.lastname: Haller
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.forename: Silke
authors.initials: S
authors.lastname: Cameron
authors.forename: Manori
authors.initials: M
authors.lastname: Beyer
authors.forename: Bastian
authors.initials: B
authors.lastname: Gunawan
authors.forename: Nicole
authors.initials: N
authors.lastname: Happel
authors.forename: Claus
authors.initials: C
authors.lastname: Langer
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ramadori
authors.forename: Anja
authors.initials: A
authors.lastname: von Heydebreck
authors.forename: László
authors.initials: L
authors.lastname: Füzesi
mesh_terms: 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
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D020033:Protein Isoforms