Originally published as JCO Early Release 10.1200/JCO.2005.02.2541 on August 8 2005

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Differential Gene Expression in Ovarian Tumors Reveals Dusp 4 and Serpina 5 As Key Regulators for Benign Behavior of Serous Borderline Tumors

Nathalie L.G. Sieben, Jan Oosting, Adrienne M. Flanagan, Jaime Prat, Guido M.J.M. Roemen, Sandra M. Kolkman-Uljee, Ronald van Eijk, Cees J. Cornelisse, Gert Jan Fleuren, Manon van Engeland

From the Department of Pathology, University of Maastricht, Maastricht; Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands; Department of Pathology, University College, London, United Kingdom; and the Department of Pathology, Autonomous University of Barcelona, Barcelona, Spain

Address reprint requests to Nathalie L.G. Sieben MD, Department of Pathology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands; e-mail: nathalie.sieben{at}path.unimaas.nl.

PURPOSE: Ovarian serous borderline tumors (SBT) are characterized by arborizing papillae lined by stratified epithelial cells, varying atypia, and absence of stromal invasion. Originally, these tumors have been classified as borderline because they behaved in a remarkably indolent manner, even with widespread tumor deposits called implants and the presence of lymph node involvement. The molecular biology of these lesions has just begun to be explored. High prevalence of B-RAF/K-RAS mutations in SBTs in contrast to serous carcinomas (SCAs) indicates that the mitogenic RAS-RAF-MEK-ERK-MAP kinase pathway is crucial for the pathogenesis of SBTs. The purpose of this study was to further unravel the genetic pathways through which SBTs develop, with a special focus on explaining the generally benign SBT behavior.

MATERIALS AND METHODS: We generated RNA expression profiles of 38 ovarian serous neoplasms. Global Test pathway analysis and significance analysis of microarrays (SAM) of the expression profiles was performed.

RESULTS: SAM and Global Testing showed that although the mitogenic pathway is activated in SBTs, activation of downstream genes involved in extracellular matrix (ECM) degradation is absent, suggesting an uncoupling of both events. In addition, we show that two genes involved in regulating this uncoupling, ERK-inhibitor Dusp 4 and uPA-inhibitor Serpina 5, are downregulated in SCAs in contrast to SBTs. In SCAs, this was associated with downstream MMP-9 activation at both mRNA and protein level.

CONCLUSION: We propose that the putative tumor suppressor genes Dusp 4 and Serpina 5 provide a major clue to the indolent behavior of SBTs.

Supported by Grant No. 920-03-050 from ZON MW, the Netherlands.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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