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Prognostic Role of E2F1 and Members of the CDKN2A Network in Gastrointestinal Stromal Tumors

Authors' Affiliations: Departments of ¹ Pathology, ² Surgery, ³ Gastroenterology, University of Göttingen, Germany; ⁴ Department of Bio- and Chemoinformatics, Merck KGaA, Darmstadt, Germany; and ⁵ Department of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Florian Haller, Department of Pathology, University of Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany. Phone: 49-551-396858; Fax: 49-551-398627; E-mail: florian.haller{at}med.uni-goettingen.de.

Purpose: The aim of the current study was to examine the prognostic relevance of the CDKN2A tumor suppressor pathway in gastrointestinal stromal tumors (GIST).

Experimental Design: 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.

Conclusion: 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.

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