Prognostic role of E2F1 and members of the CDKN2A network in gastrointestinal stromal tumors.
OBJECTIVE
The aim of the current study was to examine the prognostic relevance of the CDKN2A tumor suppressor pathway in gastrointestinal stromal tumors (GIST).


METHODS
We determined the mRNA expression of p1(INK4A), p14(ARF), CDK4, RB1, MDM2, TP53, and E2F1 by quantitative reverse transcription-PCR in 38 cases of GISTs and correlated the findings with clinicopathologic factors, including mutation analysis of KIT and PDGFRA.


RESULTS
The k-means cluster analysis yielded three prognostic subgroups of GISTs with distinct mRNA expression patterns of the CDKN2A pathway. GISTs with low mRNA expression of the CDKN2A transcripts p16(INK4A) and p14(ARF) but high mRNA expression of CDK4, RB1, MDM2, TP53, and E2F1 were associated with aggressive clinical behavior and unfavorable prognosis, whereas GISTs with a low mRNA expression of CDK4, RB1, MDM2, TP53, and E2F1 were not. GISTs with a moderate to high mRNA expression of all examined genes also seemed to be associated with unfavorable prognosis. Regarding mutation analysis, we found significant differences in the KIT/PDGFRA genotype among the three clusters. Univariate analysis revealed high expression of E2F1 to be associated with mitotic count, proliferation rate, KIT mutation, and aggressive clinical behavior. These findings on mRNA level could be confirmed by immunohistochemistry.


CONCLUSIONS
Our findings implicate differential regulation schemes of the CDKN2A tumor suppressor pathway converging to up-regulation of E2F1 as the critical link to increased cell proliferation and adverse prognosis of GISTs.
Haller
Florian
F
Department of Pathology, University of Göttingen, Germany. florian.haller@med.uni-goettingen.de
Gunawan
Bastian
B
von Heydebreck
Anja
A
Schwager
Stefanie
S
Schulten
Hans-Jürgen
HJ
Wolf-Salgó
Judith
J
Langer
Claus
C
Ramadori
Giuliano
G
Sültmann
Holger
H
Füzesi
László
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016000:Cluster Analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D005500:Follow-Up Studies; D046152:Gastrointestinal Stromal Tumors / Q000473:pathology* / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016019:Survival Analysis; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha