Originally published as JCO Early Release 10.1200/JCO.2006.08.7999 on June 11 2007

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Quantitative Gene Expression Deregulation in Mantle-Cell Lymphoma: Correlation With Clinical and Biologic Factors

Dirk Kienle, Tiemo Katzenberger, German Ott, Doreen Saupe, Axel Benner, Holger Kohlhammer, Thomas F.E. Barth, Sylvia Höller, Jörg Kalla, Andreas Rosenwald, Hans Konrad Müller-Hermelink, Peter Möller, Peter Lichter, Hartmut Döhner, Stephan Stilgenbauer

From the Department of Internal Medicine III, University of Ulm, Ulm; Department of Pathology, University of Würzburg, Würzburg; Department of Biostatistics and Department of Molecular Genetics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg; and the Department of Pathology, University of Ulm, Ulm, Germany

Address reprint requests to Stephan Stilgenbauer, MD, Internal Medicine III, University of Ulm, Robert-Koch-Straße 8, 89081 Ulm, Germany; e-mail: stephan.stilgenbauer{at}uniklinik-ulm.de

Purpose There is evidence for a direct role of quantitative gene expression deregulation in mantle-cell lymphoma (MCL) pathogenesis. Our aim was to investigate gene expression associations with other pathogenic factors and the significance of gene expression in a multivariate survival analysis.

Patients and Methods Quantitative expression of 20 genes of potential relevance for MCL prognosis and pathogenesis were analyzed using real-time reverse transcriptase polymerase chain reaction and correlated with clinical and genetic factors, tumor morphology, and Ki-67 index in 65 MCL samples.

Results Genomic losses at the loci of TP53, RB1, and P16 were associated with reduced transcript levels of the respective genes, indicating a gene-dosage effect as the pathomechanism. Analysis of gene expression correlations between the candidate genes revealed a separation into two clusters, one dominated by proliferation activators, another by proliferation inhibitors and regulators of apoptosis. Whereas only weak associations were identified between gene expression and clinical parameters or blastoid morphology, several genes were correlated closely with the Ki-67 index, including the short CCND1 variant (positive correlation) and RB1, ATM, P27, and BMI (negative correlation). In multivariate survival analysis, expression levels of MYC, MDM2, EZH2, and CCND1 were the strongest prognostic factors independently of tumor proliferation and clinical factors.

Conclusion These results indicate a pathogenic contribution of several gene transcript levels to the biology and clinical course of MCL. Genes can be differentiated into factors contributing to proliferation deregulation, either by enhancement or loss of inhibition, and proliferation-independent factors potentially contributing to MCL pathogenesis by apoptosis impairment.

published online ahead of print at www.jco.org on June 11, 2007.

Supported by the European MCL Network (Grant No. LSHC-CT-2004-503351), Deutsche Forschungsgemeinschaft (DFG; Grant No. STI 296/1-1), and Landesstiftung Banden-Württemberg (Grant No. P-LS-Prot/54).

Presented in part at the 46th Annual Meeting of the American Society of Hematology, December 4-7, 2004, San Diego, CA, and at the Gemeinsame Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften (DGHO, ÖGHO, SGH, and SGMO) für Hamatologie und Onkologie, October 2-6, 2004, Innsbruck, Austria.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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